University of Southern Denmark

Antimicrobial resistance, antimicrobial peptides and drug repurposing

Vorup-Jensen, Thomas; Hill Christiansen, Stig; Petersen, Jørgen Eskild

Published in: Microbiology Today

Publication date: 2019

Document version: Final published version

Citation for pulished version (APA): Vorup-Jensen, T., Hill Christiansen, S., & Petersen, J. E. (2019). Antimicrobial resistance, antimicrobial peptides and drug repurposing. Microbiology Today, 46(4), 174-177.

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Download date: 11. Oct. 2021 Microbiology ANNUAL CONFERENCE TODAY Microbiology Today 46:4 November 2019 November Today 46:4 Microbiology 2020 46:4 November 2019 Natural Products and Drug Discovery Drug and Products Natural

Natural Products Monday 30 March to Friday 3 April 2020 and Drug Discovery EICC Edinburgh,UK Abstracts now open Actinomycetes as nature’s pharmacists Breaking barriers with garlic microbiologysociety.org/annualconference Manuka honey: potential from beehive to bedside #Microbio20 Burkholderia bacteria: natural alternatives to synthetic pesticides Antimicrobial resistance, antimicrobial peptides and drug repurposing

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ACCESS MICROBIOLOGY_A4 ADVERT_03102019.indd 1 microb.io/ecmforumlinkedin03/10/2019 10:22 ECM SUMMER 2020_v2_A4_14102019.indd 6 15/10/2019 08:12 Editorial

Welcome to the November edition of Microbiology Today, the last one for 2019! This time we are addressing the wonderful world of drug discovery and natural products. The natural world has provided us with a huge diversity of products, which have been utilised for everything from medicine to pesticides. The sources of the natural products can themselves be from a variety of places and include products produced by micro-organisms, plants and animals. Whole Picture

he discovery of a novel molecule and the business involved in natural While prospecting around the is often the very first step in product design, Heather suggests globe in the hunt for natural products, Ta long process, leading to a how research in this field could move we sometimes forget to take a closer functional product that we then see in forward. look at what we already have. Thomas wider circulation. Our authors provide an On to a substance that needs input Vorup-Jensen, Stig Hill Christiansen insight into some of the current research from both plants and animals, Aled and J. Eskild Petersen look at how that is advancing natural products for Roberts discusses the role for honey in drug repurposing can create useful microbiology. infectious disease control, highlighting antimicrobial agents. Addressing First to take us into the world how variation between different honeys delivery, toxicity and development of natural products is Lorena affects their antimicrobial activity. costs, they demonstrate how rational Fernández-Martínez, who brings us Drawing on research which elucidates experimental design can uncover the actinomycetes. Highlighting the how manuka honey can inhibit bacteria effective antimicrobial candidates from role these micro-organisms have had in different ways, Aled addresses how compounds originally designed to treat over the years, she gives us a real this natural product could be used non-infectious diseases. appreciation of the impact these bacteria to help in the fight against antibiotic Finally, with the business end of have had in antimicrobial compound resistance. drug discovery in mind, Michael Bagnall development. Describing the diversity Next, we shift our focus from gives us the inside track on the various of products that have come from these medical to environmental, with Alex J. issues which can impact drug discovery micro-organisms, Lorena discusses Mullins and Eshwar Mahenthiralingam and natural product development from a how new culture approaches might lead explaining how Burkholderia have manufacturing point of view. Reminding to the discovery of previously hidden shown potential as natural alternatives us that discovering a promising natural compounds. to synthetic pesticides. With a growing product is only the very start of the It is not just micro-organisms world population that needs feeding, the process, Michael outlines the complex which can produce compounds with need for safe and effective pesticides and ever-evolving factors which need antimicrobial activity, and taking us from to protect food crops is becoming ever to be considered before a product can micro-organisms to plants, Heather Graz more important. Alex and Eshwar reach its intended market. gives us some insight into the research discuss the genomics which have led and development steps necessary to to the identification of key genes in Rowena Jenkins turn something like the humble bulb of these bacteria, and also the challenges Editor garlic into a registered pharmaceutical involved when designing a product that [email protected] product. Addressing both the science will be released into the environment.

Microbiology Today Nov 19 | microbiologysociety.org 149 Contents

Microbiology TODAY Articles Actinomycetes as nature’s pharmacists 158 Lorena T. Fernández-Martínez The diversity of novel bioactive compounds to be explored in actinomycetes.

Breaking barriers with garlic 162 Heather Graz The medicinal potential of garlic.

Manuka honey: potential from beehive 166 to bedside Aled Roberts The role of honey in infectious disease control.

Burkholderia bacteria: natural alternatives 170 to synthetic pesticides Alex J. Mullins and Eshwar Mahenthiralingam The benefits and challenges involved in the use of bacteria as pesticides.

Antimicrobial resistance, antimicrobial 174 peptides and drug repurposing Thomas Vorup-Jensen, Stig Hill Christiansen and J. Eskild Petersen Discovery of antimicrobial candidates from existing treatments. 46:4 November 2019 Features Regulars 157 Gill Elliott: Chair of the Virology Division 149 Editorial Find out more about the Virology Division Chair, Gill Elliott. 152 Council 2019 182 Annual General Meeting and Showcase of 153 From the President the Society’s Achievements Highlights from September’s event. 154 From the Chief Executive 183 Spotlight on grants 155 News Sabastine Arthur made use of our Education and Outreach Grant. 178 Annual Conference 2020 184 The new face of Microbiology 180 Focused Meetings 2019 Find out about the journal’s revised scope. 194 Reviews 186 Reviving the antibiotic research and development pipeline: marine natural Editor Rowena Jenkins products Managing Editor Ruth Paget Production Editor Ellen Hinkley The underwater search for antibiotics. Editorial Board André Antunes, Nigel Brown, David Blackbourn, Rachel Exley, 188 Reflections on being a member of the Lorena Fernández-Martínez, Rebecca Hall, Freya Harrison, Chloe James, Chris Randall, Nicola Stonehouse Microbiology Society Address Microbiology Society, 14–16 Meredith Street, London EC1R 0AB Hear from members about the benefits of being part of the Society. T +44 (0)20 3034 4870 E [email protected] 190 Microbiology Society and MiSAC: Design Ian Atherton, Corbicula Design (www.corbiculadesign.co.uk) 50 years of mutualism Printed by Charlesworth Press, Wakefield © 2019 Microbiology Society A look back at the relationship between the Microbiology Society and MiSAC. ISSN 1464-0570 191 ECM Forum update: Looking forward: The views expressed by contributors do not necessarily reflect official policy of the Society; nor can translating research and tackling mental the claims of advertisers be guaranteed. health Q&A with incoming Communications Representative, Robert Will. FSC Logo 192 Member Q&A Zina Alfahl tells us about her career. 193 Obituary Professor Michael Rossmann 1930–2019. 195 Comment – Industry insights in drug development Pharmaceutical research, Michael Bagnall conceptual image. Tek Image/ The drug development process at Merck Sharp & Dohme (MSD). Science Photo Library Council 2019

Executive Officers President – Professor Judith Armitage Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU; [email protected] General Secretary – Professor Maggie Smith Department of Biology, Wentworth Way, University of York, York YO10 5DD; [email protected] Treasurer – Professor Ian Roberts School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Michael Smith Building, University of Manchester, Manchester M13 9PT; [email protected]

Chairs of Committees Communications Committee – Professor Nicola Stonehouse School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT; [email protected] Early Career Microbiologists’ Forum Executive Committee – Amy Pickering The Roslin Institute, Easter Bush Campus, Edinburgh, Midlothian EH25 9RG; [email protected] Finance and Operations Committee – Professor Ian Roberts See ‘Treasurer’ above Policy Committee – Professor Paul Kellam Imperial College London, Faculty of Medicine, St Mary’s Campus, Norfolk Place, London W2 1PG; & Kymab Ltd; [email protected] Professional Development Committee – Dr Tadhg Ó Cróinín Health Science Centre, University College Dublin, Belfield, Dublin 4, Ireland;[email protected] Publishing Committee – Professor Jodi Lindsay Institute of Infection and Immunity, St George’s, University of London, Cranmer Terrace, London SW17 0RE; [email protected] Scientific Conferences Committee – Professor Mick Tuite School of Biosciences, University of Kent, Canterbury CT2 7NJ; [email protected]

Elected Members Professor David J. Blackbourn (Chair of Equality, Diversity and Inclusion Ambassadors) The School of Biosciences and Medicine, 14 AX 01, Edward Jenner Building, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH; [email protected] Professor Deirdre Devine School of Dentistry, University of Leeds, St. James’ University Hospital, Leeds LS9 7TF; [email protected] Professor Charles Dorman Department of Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin 2, Ireland; [email protected] Dr John Morrissey School of Microbiology, University College Cork, Ireland; [email protected] Professor Tracy Palmer Centre for Bacterial Cell Biology, Baddiley-Clark Building, Medical School, Newcastle University, Newcastle upon Tyne NE2 4AX; [email protected] Professor George Salmond Department of Biochemistry, Hopkins Building, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW; [email protected]

152 Microbiology Today Nov 19 | microbiologysociety.org From the President

My tenure as President is taking place as the Society turns 75, and it promises to be a year to remember. The Society’s Annual Conference will be in the beautiful city of Edinburgh in 2020. Annual Conference 2020 will be preceded by the Fleming Showcase, a celebration of microbiological science with eminent scientists speaking and discussing key topics in the field.

he event will also focus on microbiology community. We asked We would also like to welcome the future of microbiology and the community to submit a nomination more members, from across the UK Tearly career researchers will for a discovery or event that showcases and Ireland, to take an active role in the be presenting their work. Abstract microbiology and its impact in the Society to help shape what we do. The submission for Annual Conference 2020 past, the present and what current Society needs your voice and welcomes is open online until Monday 9 December, findings could lead to. These areas of and encourages members to become so do remember to submit your abstract research will be published throughout Society Champions, submit proposals to ensure you are part of the event. 2020. for Annual Conference and Focused You can also book to attend the Annual I am looking forward to the Meetings and consider how they would Conference 2020 and the Fleming upcoming Roadshow events in Plymouth like to progress their professional Showcase on the website. and Reading this month, having development by taking an active role There have been a number of hosted successful events in Leeds in groups such as the Early Career submissions for the 75th anniversary and Newcastle earlier this year, and Microbiologists’ Forum. Microbiology Images project, including in Dublin a few weeks ago. I believe As my first year as President comes my own, showing the position of some of the best science comes from to an end, I have reflected on some of proteins. Images can be easier to share unexpected collaborations. I hope to the Society initiatives and events that and help explain the context of research; encourage as many microbiologists have enabled me to talk directly with they can inspire and engage people as possible, not necessarily just microbiologists to find out more about who may not know how intricate and members, to come together locally to their work. Being part of these activities visually stunning microbes can be, or foster new connections, and, with the has been incredibly enjoyable and how science is done. We would also like support of Society staff, encourage rewarding. 2019 has been a significant to capture the wider context of your more engagement in Society activities. year, and the Society headquarters has research and welcome submissions in I know from the 2018 Membership also moved to a new office to allow the the following categories: people, science, Survey that localness is important to the Society to better meet the ambitions and nature, places, laboratories. The images membership and building collaborations needs of the microbiology community. will be shared throughout 2020 to is a key element of science research. The Society is going from strength to showcase the work of members and the By attending one of the events you will strength and I am looking forward to microbiology community, to introduce also enable me to understand what seeing what the next two years will other microbiologists and the wider else the Society might be able to do to bring. public to your research and the field of support you. There will also be further microbiology. Roadshow events during 2020 as part Judith Armitage We will also launch the Why of our anniversary celebrations and I President Microbiology Matters project in 2020, am looking forward to the opportunity to [email protected] based on the submissions from the host these in new locations.

Microbiology Today Nov 19 | microbiologysociety.org 153 From the Chief Executive

It was a great pleasure at the Microbiology Society’s Annual General Meeting to report to the membership about the range of impressive work in recent months. Those efforts are all about strengthening the networks available to the members of the Society, promoting your work and its contribution to society, and making sure that we have robust plans for the future.

hose future plans are ambitious Career Microbiologists’ Forum has rapidly The Microbiology Society has and exciting, and they draw on become established as a vehicle for its changed a great deal in recent years, and Tthe Society’s core strengths – constituency to participate in our decision- these ambitious aims for the future will the experience and knowledge of the making. But there are many other ways mean more change to come. They are not members and the professional expertise in which we are moving to empower just possible, but also highly successful, of the staff. It is this knowledge and sections of the microbiology community. because at its core, in its fundamental expertise, applied in innovative ways, that For example, our work to help inform purpose and its beliefs, the Society has will allow microbiology to make an ever- discussions about the future strategy of been unwaveringly constant throughout bigger contribution to the world around us. Science Foundation Ireland is, for the first its history. Next year – 2020 – will see our To deliver these ambitions, we need to time, giving Irish-based microbiologists a 75th anniversary, and we will collectively be better at two things. First, we need to specific and coherent voice in discussions celebrate why microbiology matters. build the strongest possible relationship about their future funding opportunities. As we do so, it is worth remembering between the staff and the members, and The other thing we need to get what our far-sighted founders set out to over recent months and years, we have better at is closing the gap between the achieve. These were scientific greats like taken a variety of steps in this direction. Microbiology Society and other groups Nobel Laureate Alexander Fleming and Some of these are very obvious, like the and organisations who share some of our Marjory Stephenson, one of the first two President’s Roadshow events, where aims. Some of these will be scientific in women elected to the Royal Society. Time members of the staff team accompany nature, and it has been really valuable to and again, their early meetings stressed the President around the UK and Ireland build partnerships and joint activities with the importance of “interconnections” to meet directly with members and the Irish Fungal Society, Protistology-UK among different microbiologists and the prospective members. Other initiatives and the British Yeast Group. But other strength that comes from harnessing may be less obvious – for example, we important organisations will include these links. As we approach our 75th have recently brought the administration public bodies, private companies and birthday, we live in very different local of the peer review process back in-house charities in other sectors. Our project and global circumstances from those for most of our journals. This means on ‘A Sustainable Future’ aims to of our founders, but by focusing on the that if you need to communicate with demonstrate the value and raise the same objectives, the Microbiology Society someone during that procedure, it will be profile of microbiology in addressing the is well placed not just to celebrate its a member of Microbiology Society staff, world’s greatest challenges. It will be past but to look forward to an impressive who understands the community and most successful where we are able to and successful future. the organisation, not someone from an build common cause with the government outsourced company. agencies and non-governmental Peter Cotgreave We are also redoubling our efforts to organisations that are closest to the Chief Executive give a voice to all the different subsets of work of delivering the United Nations [email protected] the microbiology community. The Early Sustainable Development Goals.

154 Microbiology Today Nov 19 | microbiologysociety.org News

New microbiologyresearch.org The Microbiology Society journals have a fresh new look following an upgrade to the publishing platform in August. The whole Society

archive, covering more than 70 years and 60,000 articles, can be ck sto hink found at alongside the very latest content _ist/T microbiologyresearch.org rabbit75 from our six journals. Our journals are an important part of our mission to advance 2020 Prize Lectures the understanding and impact of microbiology, both in themselves We are delighted to announce the 2020 Prize as places to publish research and through their vital financial Lecture winners, who will all be presenting at contribution to the Society, and member Annual Conference in Edinburgh: support is vital to their continuing 2020 Prize Medal health. You can help by submitting Professor Martin Blaser articles, volunteering as a reviewer Rutgers University, USA or editor, or simply letting your institutional librarian know that 2020 Fleming Prize

you value the Microbiology Society Professor Edze Westra

journals. University of Exeter, UK

D en For more information nis Ku nke about supporting the journals, email 2020 Marjory Stephenson Prize l Mi crosc rary opy/Science Photo Lib [email protected]. Professor Julian Parkhill FRS University of Cambridge, UK Society signs Open Access deal with UK Higher 2020 Peter Wildy Prize Education consortium Professor Graham Hatfull University of Pittsburgh, USA With Wellcome Trust and UKRI endorsement, we are excited to announce a new Open Access (OA) initiative between the 2020 Unilever Colworth Prize Microbiology Society and Jisc Collections, the UK Higher Education Professor Manu Prakash library consortium. Stanford University, USA What does it mean for our UK members? So long as your university opts-in to our Publish & Read deal with Harry Smith Vacation Studentships Jisc, articles where you are a corresponding author and which are Applications for support for undergraduate research accepted by any of the Society’s six journals will be published OA projects during Summer 2020 will open on 2 without further cost to you, your department, your faculty, or your December 2019. library. At the same time, everyone at your university will be able Applications should be submitted by the to read all the paywalled content from the Society’s subscription supervisor, and successful applicants will receive journals. support for their research project in the form of a What about members from outside the UK? stipend, as well as the chance to apply for a bursary Watch this space. We are discussing Publish & Read deals with other to present the results of their projects at the Annual national consortia and with individual university libraries. Conference 2021.

Microbiology Today Nov 19 | microbiologysociety.org 155 Federation of Infection Societies Microbiology Society President Conference 2019 (FIS 2019) could be coming to a 11–14 November 2019, EICC, UK location near you The Microbiology Society is delighted to be Following on from the hosting the Federation of Infection Societies successful Roadshow Conference 2019 (FIS 2019) in Edinburgh events hosted at the between 11 and 14 November 2019. University of Leeds, This event is a unique conference which Newcastle University includes the collaboration of 16 societies across and Trinity College the UK with interests in different aspects of Dublin earlier this year, infectious diseases, clinical microbiology, this autumn Society President biomedical science and infection control. It Professor Judith Armitage will provides a great opportunity to find out about continue her journey around the UK and Ireland to engage with members the latest developments and to connect with of the Society. You will find Judith at the following locations: key contacts and networks. • 18 November University of Plymouth, UK The sessions cover some of the most • 26 November University of Reading, UK important current issues facing infectious disease Members and non-members are welcome to join these FREE control, prevention, diagnosis and treatment. events which unless stated will usually take place between 15:00 and 17:00. There will be the chance to do the following at each event: • Meet the President, Professor Judith Armitage. • Engage in interactive, topical discussions. • Network with local like-minded individuals. • Find out why microbiology and being part of the Microbiology Society matters. • Learn how you can get more involved in Society activities, including our 75th Anniversary in 2020. • Meet the Microbiology Society team. For more information please contact Erin Taylor at evenfh/iStock [email protected]. Grant deadlines

Date Grant 1 December 2019 Travel Grants for members presenting at conferences from 1 January 2020. 20 January 2020 Society Conference Grants for early career members presenting at Annual Conference 2020. Also, for technicians or retired members and members requiring support for caring costs. 10 February 2020 Harry Smith Vacation Studentships to support undergraduate research projects during summer 2020. For more information please visit the website (microbiologysociety.org/grants).

Connect with the Microbiology Society on social media:

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156 Microbiology Today Nov 19 | microbiologysociety.org Gill Elliott Chair of the Virology Division

The Society has four Divisions (Eukaryotic, Prokaryotic, Virology and Irish) which consist of Society members who support the organisation and plan sessions and symposia for the Society’s events programme. Each Division Chair and Chair- Elect sit on the Scientific Conferences Committee and the Chair reports into the Society’s governing body, Council. In this article we find out more about Gill Elliott, Chair of the Virology Division.

am Professor of Virology and Research virology by my supervisor Bert Rima, Director in the Department of Microbial and I discovered the joy of research at ISciences, University of Surrey, UK. the bench. I was hooked instantly, and My major research interest is the still am. cell biology of herpesvirus infection, Elliott Gill primarily of herpes simplex virus. When did you join the Society of the scientific content of the virology My lab pioneered the development and why did you join? part of the Annual Conference, and to of fluorescent viruses to image virus I first joined the Society when I was a work with my Chair-Elect to co-ordinate infection in real time. Viruses are PhD student – many years ago! It was the symposia and workshops that the fantastically powerful cell biology tools, a great opportunity to attend a broad- Division organises. I work with a great and we use them to understand not only scope conference on a relatively low team of UK and Irish virologists on the the virus in question, but also the cells in budget, to hear work presented by top Division to come up with stimulating which they grow. virologists and to network with other programmes of science, which are PhD students. I always ensure that my delivered by internationally renowned When did you first decide you own PhD students are able to attend the speakers. As Chair of a Division, I also sit wanted to do science (and why)? Annual Conference and experience the on the Society’s Scientific Conferences For as long as I can remember I same opportunities. Committee, which brings me into close have been fascinated by the world of contact with the other Divisions in the science – from experimenting with a Please describe your role on Society and enables me to contribute chemistry set as a ten-year-old to using the Division. to the broader decisions made by my brother’s rudimentary microscope I am currently Chair of the Virology the committee, helping to shape the to look at onion cells. My interest in Division. My role is to have oversight conferences in recent years. microbiology began in secondary school, when we learnt about the work Are you a member that would like to join one of the Divisions? of famous scientists such as Louis Find out more about the Divisions and what they do on our website Pasteur and Edward Jenner. Viruses (microbiologysociety.org/divisions). The Council and Committees shadowing came much later; in fact, not until my scheme (microbiologysociety.org/shadowingscheme) is also a fantastic final year undergraduate project at opportunity to gain an insight into the work of the Society and gain first-hand Queen’s University Belfast. There I was experience of our Council and Committee activities. introduced to the field of molecular

Microbiology Today Nov 19 | microbiologysociety.org 157 Actinomycetes as nature’s pharmacists

Lorena T. Fernández-Martínez Fig. 1. Streptomyces coelicolor producing actinorhodin, a blue-pigmented antibiotic. Edge Hill University photos The increasing incidence of antibiotic-resistant bacterial pathogens has resulted in an urgent need for new, clinically useful antibiotics. By 2050, antibiotic-resistant micro- organisms are expected to cause more deaths than cancer, road traffic accidents and other chronic diseases worldwide.

his is partly because effective drugs that can be used in the clinic are antibiotics are essential to still required. Tprevent infection when carrying out life-saving medical procedures Where do our antibiotics come from? such as surgery and chronic illness Soil micro-organisms have always been management. While reduction of seen as a great resource for discovering antimicrobial use in farming and not only antibiotics but also a broad increased antibiotic stewardship are range of other bioactive natural products both essential, new viable alternative with antitumoral, immunosuppressant,

158 Microbiology Today Nov 19 | microbiologysociety.org antifungal and anthelminthic activity. natural product discovery field to start a diverse array of natural enemies, Amongst soil micro-organisms, exploring more unusual environments most of which are fungal pathogens. actinomycetes are the most prolific in the hope that novel strains containing Examples of talented actinomycetes, in Actinomycetes producers of bioactive natural products. new antibiotic gene clusters with terms of specialised metabolite diversity, Actinomycetes are ubiquitous bacteria potential clinical use will be identified. isolated from leaf cutter ants to date and, as such, they can be found in most In recent years, the astonishing belong to genera such as Rhodococcus, environments on Earth. diversity of natural products from Nocardia, Microbacterium, Kitasatospora, as nature’s actinomycetes found in marine Pseudonocardia and Streptomyces such Streptomyces were the initial environments has become apparent. as Streptomyces formicae KY5, producer antibiotic makers Over 250 novel bioactive compounds of a group of pentacyclic polyketides pharmacists Most of the antibiotics used in medicine have been reported from approximately known as formicamycins which present and veterinary settings are produced 100 different actinomycete strains, antibacterial activity against multidrug- by actinomycetes, a fascinating group belonging to nearly 40 different genera, resistant strains. of non-motile filamentous bacteria. The in the last decade. Among them, genera This is only a small sample of most prolific producers of antimicrobial such as Salinispora, with over 40 novel the chemical diversity of bioactive compounds, responsible for the compounds identified including the specialised metabolites encoded in the production of over two-thirds of these medically relevant salinosporamides; genomes of actinomycetes isolated clinically relevant molecules, belong Verrucosispora, with 18 new compounds worldwide to this point. to the genus Streptomyces, which is identified including the abyssomicin abundant in all soil environments. family of antibiotics; Nocardiopsis (52 Increasing yield is essential During the period from 1950–1970, new compounds) and Micromonospora in order to produce a successful known as the Golden Age of antibiotic (46 new compounds) are showing drug candidate discovery, soils were intensely screened remarkable potential as sources of The development of improved next by the pharmaceutical industry in structurally diverse, novel, specialised generation sequencing and mass order to isolate antibiotic-producing metabolites with both unique chemical spectrometry technology, as well micro-organisms including mostly moieties and clinically relevant activities. as bioinformatic programmes able Streptomyces species and other closely The Atacama Desert of northern to identify specialised metabolite related actinomycetes genera. This Chile, considered to be one of the most biosynthetic gene clusters has approach resulted in thousands of drugs arid and extreme environments on Earth, emphasised the vast genetic potential of being identified during this period, and has also proven to be an unexpectedly actinomycetes as nature’s pharmacists. later applied to the clinic, including a rich resource of actinobacterial and In fact, their potential to produce variety of antimicrobial compounds. novel chemical diversity. A total of 46 specialised metabolites is far more than However, after just a couple of decades, secondary metabolites representing initially revealed by traditional screening. rediscovery of specialised metabolites diverse chemical classes including In order for any promising bioactive became a regular occurrence and the alkaloids, peptides, macrolides, compound to undergo clinical trials, rewards from this type of strategy were terpenes and polyketides such as the it is critical to obtain high enough substantially reduced. novel antimicrobials chaxalactins and levels of the drug. The challenge most chaxamycins, are derived from only a actinomycetes geneticists face is to find Screening new environments few Streptomyces strains isolated so far efficient ways to increase the yield of could lead to the discovery of from that environment. these potential candidates, particularly new antimicrobial compounds Actinobacteria associated with the those compounds for which biosynthetic Screening similar environments in cuticle of different species of leafcutter gene clusters are encoded in the search of actinomycetes tends to lead to ants have been identified in recent years genome but production levels are barely the isolation of micro-organisms which as extraordinary reservoirs of bioactive detectable under laboratory conditions. produce structurally similar antibiotics. molecules which assist leafcutter ants in Based on their genome sequences, This has encouraged scientists in the protecting their fungus gardens against most actinomycete species have the

Microbiology Today Nov 19 | microbiologysociety.org 159 potential to produce on average around 10–15 antimicrobial agents of natural product origin. However, when these species are grown under laboratory conditions, only one or two antimicrobial compounds are usually detected. This is because most of these antibiotic gene clusters appear dormant (i.e. are not expressed) under laboratory conditions. The fact that actinomycete species maintain these intact antibiotic gene clusters in their genomes suggests the products are useful in nature, probably to attack competitor micro- organisms in their harsh environments. These dormant or cryptic antibiotic gene clusters represent an untapped resource in terms of novel chemistry which could lead to the discovery of new antimicrobial compounds that could be very useful in the clinic if we were able to produce them in high enough amounts. There are several ways in which scientists can ‘awaken’ and increase production of these silent gene clusters. One of these key approaches is to understand the regulation of specialised metabolite gene clusters. By growing actinomycete strains under conditions similar to those they would encounter in their natural environment, scientists can understand the signalling pathways leading to the expression of these compounds and later manipulate them in the laboratory. Identifying the role of regulatory proteins ultimately controlling the production of a novel antimicrobial compound allows scientists to manipulate biosynthetic pathways using a rational approach; i.e. overexpression of positive regulators and/or deletion of negative regulators from the genome, hopefully leading to increased yield of the compound. The recent development of actinomycete genetic tools which Fig. 2. Actinomycetes isolates from soil samples worldwide. Lorena Fernández-Martínez.

160 Microbiology Today Nov 19 | microbiologysociety.org generate clean deletions of genomic Hopwood DA. Streptomyces in Nature and product diversity of actinobacteria in the regions such as the SceI meganuclease Medicine. Oxford: Oxford University Press; Atacama Desert. Antonie van Leeuwenhoek system and the pCRISPomyces plasmids 2007. 2018;111(8):1467–1477. have considerably facilitated this task. O’Neill J. Tackling Drug Resistant Infections Sayed AM, Hassan MHA, Alhadrami HA, Hassan Another tactic to enhance production Globally: Final Report and Recommendations HM, Goodfellow M et al. Extreme environments: of specialised metabolites involves 2016. microbiology leading to specialised increasing the availability of precursors Palazzotto E, Tong Y, Lee SY, Weber T. metabolites. J Appl Microbiol 2019;DOI:10.1111/ in the media so as to encourage induction Synthetic biology and metabolic engineering of jam.14386 [Epub ahead of print]. of biosynthetic gene clusters, and finally, actinomycetes for natural product discovery. Subramani R, Sipkema D. Marine rare cloning entire biosynthetic gene clusters Biotechnol Adv 2019;37:107366. actinomycetes: a promising source of into heterologous hosts has also proven Qin Z, Munnoch JT, Devine R, Holmes NA, structurally diverse and unique novel natural successful. Heterologous expression Seipke RF et al. Formicamycins, antibacterial products. Mar Drugs 2019;17:249. has the advantage of removing global polyketides produced by Streptomyces van der Meij A, Worsley SF, Hutchings MI, transcriptional ties present in the natural formicae isolated from African Tetraponera van Wezel GP. Chemical ecology of antibiotic producer, but good understanding of plant-ants. Chem Sci 2017;8:3218–3227. production by actinomycetes. FEMS Microbiol the metabolic resources and regulatory Rateb ME, Ebel R, Jaspars M. Natural Rev 2017;41:392–416. cascade required for the production of these ‘silent’ pathways in the natural Lorena T. Fernández-Martínez producer also needs to be considered in Reader in Microbial Genetics, Biology Department, Edge order to successfully obtain high yields Hill University, Ormskirk L39 4QP of the compound of interest. @lore_fermar edgehill.ac.uk/biology/research/ Future perspectives actinomycetes-biology-antibiotic-discovery Actinomycetes are ubiquitous Lorena Fernández-Martínez studied a BSc in nature’s pharmacists which provide Fernández-Martínez T. Lorena Genetics and Biochemistry before completing a PhD us with a plethora of novel bioactive on the regulation of stress responses in the bacterial genus Streptomyces. compounds to be explored. It is through She then moved to postdoctoral positions at INBIOTEC, Spain and John Innes interdisciplinary collaborations and Centre, UK. Her research at Edge Hill University focuses on understanding the innovative ideas that we will continue to complex regulatory pathways that lead to specialised metabolite production in unlock their potential and keep ahead on actinobacteria by using gene manipulation, co-cultivation and environmental the antimicrobial resistance arms race. extracellular signalling methods. Lorena has been a member of the Microbiology Society for 17 years. Further reading Alberti F, Corre C. Editing streptomycete Why does microbiology matter? genomes in the CRISPR/Cas9 age. Nat Prod Rep DOI:10.1039/C8NP00081F [Epub ahead Micro-organisms are essential for life on Earth. Understanding microbiology of print]. helps us understand environmental and ecological interactions on the planet, Castro JF, Razmilic V, Gomez-Escribano the evolution of living organisms, plant and animal health (including humans), as JP, Andrews B, Asenjo J, et al. The ‘gifted’ well as providing biotechnological solutions to current problems. That’s why all actinomycete Streptomyces leeuwenhoekii. aspects of microbiology are so important and worth studying. Antonie van Leeuwenhoek 2018;111: What is the best career decision you have ever made? 1433–1448. I think one of the best decisions in my career was joining the Microbiology Fernández-Martínez LT, Bibb MJ. Use of Society Communications Committee, as it has given me the opportunity to meet the meganuclease I-SceI of Saccharomyces fantastic people working in completely different aspects of microbiology, who are cerevisiae to select for gene deletions in now friends and collaborators. actinomycetes. Sci Rep 2014;4:7100.

Microbiology Today Nov 19 | microbiologysociety.org 161 Almost every day there is another news Breaking headline calling for new, effective and affordable barriers treatments for many of the diseases that are with prevalent in society. Non- communicable diseases such as ischaemic heart garlic disease, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), respiratory cancers and diabetes have been named as diseases needing new treatments.

Heather Graz nfectious diseases such as lower cancer, cardiovascular disease and respiratory tract infections and infectious disease. On first thought, Ituberculosis are also highlighted this apparent alignment between a in public health literature as leading problem and a possible solution sounds causes of death, for which new and like a cinch. But do these reports of more effective treatments are needed if garlic’s health benefits stand up to the effects of global health crises, such scientific scrutiny so that we can use as antimicrobial resistance, are to be them as part of a solid evidence base circumvented. for developing new treatments? And The reported health benefits of if so, what needs to be considered to garlic are wide-ranging and touch transform a lowly clove of garlic into a on many of these diseases, including credible, pharmaceutical intervention

162 Microbiology Today Nov 19 | microbiologysociety.org Breaking barriers with garlic

Heather Graz Molecular model of allicin. topthailand/iStock that complies with the drug Basic research and discovery vitro work is carried out in laboratory development standards of modern- Early drug development starts when, settings and starts to shed light on day healthcare? during hit identification stages, if and how compounds may work. compounds are identified that show In garlic, as in most other The drug development process potential to act upon a particular natural products, numerous interacting A starting point to answer these symptom or disease. These hits are compounds are present in varying questions lies in the nature of refined and improved during subsequent amounts across samples. This translates contemporary accepted drug hit optimisation, hit-to-lead and lead into a likelihood that a given compound development processes and in an optimisation experimentation stages, may exhibit several interrelated understanding of how natural products yielding compounds that can be selected mechanisms of action. For long-term and their processing relate to these to be taken into more in-depth and scientific research, this holds much requirements (Fig. 1). expensive pre-clinical studies. This in promise. In current drug development

Microbiology Today Nov 19 | microbiologysociety.org 163 Basic research Lead User Clinical Commercialisation (hit identification) optimisation input studies

Hit Preclinical Hit-to-lead CMC optimisation studies

Fig. 1. Sequence of stages in the contemporary pharmaceutical drug development process. Heather Graz

practice, it complicates the process of Pre-clinical studies Chemistry, manufacture and controls isolating a specific target compound During the pre-clinical stage, data Chemistry, manufacture and controls for further testing and generating on dosing, metabolism of the compound (CMC) ensure that adequate amounts repeatable and acceptable data for and the compound’s toxicity is of optimised and approved compound regulators. generated for use in clinical studies. are manufactured for use in upcoming While some advances have been Dosage is key when working with garlic, clinical studies. This requires know- made in understanding some of the to avoid the corrosive and toxic effects how in scaling up, from lab-scale mechanisms by which garlic exerts its that the bioactive compound allicin experiments into commercial production. influence, large gaps in our knowledge and its degradation product, ajoene, Robust and regulated quality assurance remain about how its complex and can have. and control processes need to be in multifaceted chemistry works with other The question of how to get enough place. chemistry and in biological systems. of the active molecule into the right Key issues to consider during This is key in being able to refine the place in the human body is another CMC include how best to formulate design of subsequent experiments vital consideration. As it is originally your compound for delivery and and strengthen one’s data package. of plant origin and a source of food uptake in humans. This is particularly Innovative technologies and techniques for humans, garlic’s health-inducing important when working with garlic, such as fluorescence imaging, high- compounds, such as allicin or ajoene, as its active compounds break up and throughput screening, microfluidics and are easily and quickly broken up by degrade easily when they come into computational chemistry advances are the human body. This means that contact with mammalian tissue, limiting helping to bridge these gaps. limited amounts of the compounds bioavailability of the targeted compound. Although not universally done, it is remain for long enough to be able Economic factors such as cost always better to seek feedback from to be taken up by the body and per dose administered and ease of end-users of the envisioned end product. harnessed for medicinal purposes. manufacture also come into play here. Early discussions with patients and This introduces a conundrum of Conversion of natural product extracts clinicians help to avoid wasting time balancing volume, concentration of into druggable compounds is often and money on developing a product bioactive molecules and the best complex and costly and it may therefore that people will not use. With garlic, this delivery mechanism to achieve the not make business sense to proceed. is even more important. Garlic evokes best effect, without causing adverse strong emotions – people either love it effects. This is as much an art as it is Clinical studies or hate it – so concerns about odour or a science to develop a pharmacologically This stage evaluates the safety and taste have to be addressed. active dose. efficacy of the compound in a human

164 Microbiology Today Nov 19 | microbiologysociety.org body rather than in a test tube. A way forward? a better question. Advances in This is key as it opens the door for So, can garlic be developed into an microbiological, chemistry and data further product development and approved medical intervention for science technologies may offer commercialisation. animal or human use? Conventional scope to strengthen this evidence Medicinal regulatory authorities wisdom would suggest that at least at base and break new ground in our globally are, however, often hesitant to conceptual level, this should be possible, understanding of garlic’s chemistry accept medical interventions that are at some point in time. and biology interactions and potential based on natural products. Variable We are not starting from a strong for druggability. Perhaps the question amounts and concentrations of evidence base, however, with lack of needs to be whether developing garlic bioactive compounds across testing and detail about the compound composition as a medicine can be part of a broader manufacturing batches make it difficult of garlic extracts used, variations in innovation in a science–business– to obtain repeatable results during rigour of experimentation processes healthcare triad. Now that would be a development. Multiple mechanisms of and short duration of studies being high-impact breakthrough.

action also reduce the ability to explain a common criticisms of many of the

single compound’s mechanism of action studies that have looked at garlic’s Further reading unequivocally. In practice, this means health effects. Block, E. Garlic and Other Alliums. The Lore that there are no accepted processes for From a glass-half-full perspective, and the Science. Cambridge: Royal Society of guiding development of natural products perhaps the answer lies in asking Chemistry; 2010. that are readily available to regulators, potentially requiring developers to Heather Graz

carry out more extensive testing and Chief Operating Officer, Biophys Ltd increasing the cost of a compound’s e [email protected] development. Heather Graz has an MBA from Exeter University For many companies, such increased and before that almost 25 years of experience in cost could make the difference between direct patient care and business management. She success and failure to achieve drug transitioned into the biotechnology sector and has been

approval with their compound. Heather Graz responsible for managing commercial aspects of plant-

“ based drug development for the past five years.

Advances in microbiological, What advice would you give to somebody starting out in the field of chemistry and data science pharmaceutical drug development? Pharmaceutical drug development is a high risk but potentially high-impact technologies may offer scope field. It is complex and fascinating, and we are all only one cog in a very large machine. Be willing to start at the bottom, keep an open mind and learn to strengthen this evidence as much as you can from the experienced people around you. Above all, base and break new ground remember to keep the patient, who will benefit from a successful treatment, at the forefront of what you do. They are the ultimate reason that we do what in our understanding of we do. garlic’s chemistry and biology What is your greatest achievement to date? Learning a completely new business skill set as a mature student and interactions and potential for merging this with 25 years of prior direct patient treatment experience in a career transition from frontline speech and language therapy to managing druggability. commercial aspects of novel drug development in the biotechnology “ industry.

Microbiology Today Nov 19 | microbiologysociety.org 165 Antibiotics have been a cornerstone of medical treatment since they were first introduced in the 1940s. They’ve allowed transmissible infections to be treated and opened up the possibility of more invasive medical procedures. However, the impending antimicrobial resistance crisis is set to undo all of this. In a post- antibiotic era, can manuka honey, a natural product with a successful past, undo this sticky situation?

Aled Roberts Manuka honey: potential from beehive to bedside

166 Microbiology Today Nov 19 | microbiologysociety.org Sticky situation surrounding for our children which has since put the product made from the constitutes antimicrobial resistance impending AMR crisis at the forefront of its surroundings, there are many The emergence of antimicrobial of science policy and political debate different types and, more recently, the resistance (AMR) was all but within the UK. Now, we are regularly medicinal properties of these have been prophesised by Alexander Fleming reminded in some form or another of investigated. in the 1940s following the clinical the impending AMR crisis (and quite introduction of penicillin, and by the late rightly so!). More recently, small biotech So, is all honey created equally? 1990s and early 2000s the downfall of companies and academic researchers Well yes and no. Honey is a natural ‘Big-Pharma’s’ antibiotic drug discovery alike are pursuing the antibiotic mantle product with a complex chemistry that pipeline was all but certain. Too few once held by ‘Big-Pharma’, searching contains up to 600 unique compounds. people outside of academic circles for the next generation of antimicrobials However, 97% of its weight is made took note and the wider community in the most unlikely places. One such up from four simple sugars (fructose, was unaware until the tireless work of place gaining increased interest of late glucose, maltose and sucrose) and Dame Sally Davies and Lord Jim O’Neill. is the beehive, and more specifically, water. These ‘non-variable’ components Together they have painted bleak futures the honey contained within. As a natural are consistent across all honey types, giving rise to the characteristic sweetness and self-preserving qualities. Aled Roberts Manuka honeycomb. welcomia/iStock The sugars achieve this by reducing the pH and water activity of the honey to a level where growth is prohibited, but this antimicrobial effect is short lived when the honey becomes diluted. The remaining 3% is a ‘highly-variable’ mixture of minerals, oligosaccharides, organic acids, phenolic compounds, proteins and vitamins which are produced by plants and incorporated into the nectar (along with the sugars). Therefore, the exact cocktail of compounds present within a honey is representative of the botanical source (and growth conditions) from which the nectar was gathered, giving rise to honeys with distinctive tastes, colours, and aromas. More importantly (at least in the context of this article) these botanical compounds can increase the overall antimicrobial activity of the honey, even when it becomes diluted. This increased antimicrobial activity is not a certainty and has led to the identification of some honeys that are more potent than others, gaining them notoriety within the field. Manuka is one such honey that was identified in the mid 1980s as having

Microbiology Today Nov 19 | microbiologysociety.org 167 exceptional antimicrobial activity that was retained upon extensive dilution. This activity is due to the incorporation of manuka bush botanics into the honey. One key compound is methylglyoxal, which is derived from dihydroxyacetone in the starting nectar. It is believed that this is responsible for the majority of manuka honey’s antimicrobial activity and the evidence suggests there are other as yet unknown compounds that modulate activity.

Inhibitory effects to unstick the

AMR crisis? Recently, researchers have tried to better understand the antimicrobial activity of manuka honey, identifying the mechanism by which it inhibits bacterial cells and the compounds responsible

for this activity. Two distinctly different mechanisms have been identified to date against two unique bacterial species. Against Staphylococcus aureus, a notorious Gram-positive nosocomial pathogen, manuka honey arrests the Manuka flower.purefocus/iStock latter stages of the cell division process

(post septa-formation between daughter unclear. Importantly, these inhibitory “ cells) resulting in the death of daughter effects are not confined to planktonic For manuka honey at least, cells. Conversely, against Pseudomonas culture, with observable inhibitory effects aeruginosa, an inherently difficult to treat seen against biofilms and chronic in vivo all previous in vitro attempts Gram-negative pathogen, manuka honey infections. As a product with broad- to generate resistance have destabilises the cell envelope (down- spectrum activity, it makes an excellent regulating cell wall anchor proteins) candidate for the initial treatment of been unsuccessful … and leading to membrane blebbing, which infections, particularly where the exact there are currently no reports eventually results in cell lysis. It is causative agent isn’t known immediately. unclear if these mechanisms are finite, Even when manuka honey is diluted of in vivo resistance, most representing species-specific interactions, beyond its inhibitory concentration, it or if they form a broader inhibitory action still retains some activity, attenuating a likely due to the presence of that is Gram-specific. What is certain wide range of virulence traits in various multiple selection pressures is that manuka honey has the ability to bacterial species. inhibit a wide range of clinical pathogens from a wide range of such as Acinetobacter, Burkholderia, Is the future bright, is the future botanical compounds exerting Enterococcus, Listeria, Salmonella, Shigella golden? and Streptococcus species, even though The majority of these effects have “some effect. the mechanism against them remains been observed in vitro. However, there

168 Microbiology Today Nov 19 | microbiologysociety.org into sino-nasal wash solutions in vitro attempts to generate resistance can improve culture negativity in have been unsuccessful (although chronic rhinosinusitis patients, while increased tolerances by biofilms have in vitro combinational therapy has been reported) and there are currently proven successful against many no reports of in vivo resistance, most bacterial species. Various studies into likely due to the presence of multiple combinations of antibiotics and selection pressures from a wide range manuka honey have shown that it of botanical compounds exerting some can help some antibiotics overcome effect. As we understand it today, this resistance mechanisms to the point complex chemistry is key to its broad- where they become effective once spectrum activity, anti-biofilm effects again. and virulence attenuation. It is clear Regardless of any headway we that the future for manuka honey is make in antimicrobial research going looking bright as we move ever closer forward, if antimicrobial resistance to elucidating additional mechanistic is soon to follow then any progress is effects, identifying additional novel futile. It is therefore crucial that future compounds within manuka honey that antimicrobials are vigorously tested for have therapeutic significance and push their ability to generate spontaneous manuka honey into a clinical setting via resistance among clinical pathogens. in vivo testing. Only time will tell if it is For manuka honey at least, all previous golden.

Aled Roberts Postdoctoral Researcher, Microbiology and Infectious Disease Group, Institute of Life Sciences, Swansea Manuka flower.purefocus/iStock University Medical School, Swansea SA2 8PP, UK e [email protected] is a clear need to design robust in @sbi5ar vivo clinical trials and build upon Aled Roberts is a Hodge Foundation-funded

growing anecdotal evidence and Roberts Aled Postdoctoral Researcher in Dr Rowena Jenkins’ small in vivo case studies. One of the laboratory. He completed a PhD detailing the mechanistic effects of manuka biggest hurdles which currently limits honey on Pseudomonas aeruginosa and his current research interests focus its clinical applicability is the effective on the potential use of natural products to combat antimicrobial resistance in delivery of manuka honey to the multiple human pathogens. infection site. While this is of limited concern in surface wounds (which popularised the clinical use of manuka What skills are required in your position on a day to day basis? honey in the first place), it becomes A range of skills are required to complete my job, from aseptic techniques to the increasingly tricky to deliver manuka use of specialised equipment. However, one of the most widely used skills is that honey at effective concentrations within of patience, especially when things start going wrong! the body. Developing novel delivery What do you do in a typical day/week? mechanisms or incorporating manuka A typical week for me includes planning and conducting various experiments in honey into pre-existing clinical products the lab, and if they don’t work (which they inevitably don’t), I have to troubleshoot may aid its clinical transformation. the problems and find a solution. The rest of the week is filled with paperwork, For example, in vivo studies have reading and, most importantly, coffee! suggested that its incorporation

Microbiology Today Nov 19 | microbiologysociety.org 169 Burkholderia bacteria: natural alternatives to synthetic pesticides

initial discovery in 1952 as the cause of onion rot, Burkholderia bacteria were Alex J. Mullins and Eshwar Mahenthiralingam associated with pathogenicity. The majority of research on these bacteria Micro-organisms have fascinating lifestyles and many has focused on understanding the species most associated with disease of those that live in the natural environment carry out (Fig. 2): the Burkholderia pseudomallei beneficial or detrimental functions depending on the group as primary pathogens; the Burkholderia cepacia complex as situation in which they find themselves. Gram-negative opportunistic pathogens well known for causing lung infections in people with Burkholderia represent one group of bacteria with exactly cystic fibrosis (CF); and the Burkholderia gladioli group of plant pathogens. these ‘Dr Jekyll and Mr Hyde’ tendencies. However, all Burkholderia are capable of living freely or as symbionts in the he major negative effect However, renewed interest in these natural environment, and are not always Burkholderia are known for is bacteria as a source of natural products found associated with infection. Tinfection within a range of hosts and antibiotics, coupled with a greater Recent taxonomic analysis has including humans, animals and plants; understanding of their diversity and split Burkholderia further, defining the in contrast, they also mediate highly genomics, has provided an opportunity novel genus Paraburkholderia (Fig. 2). beneficial interactions. A timeline of to repurpose Burkholderia as safe Paraburkholderia species are rarely these positive and negative traits, biopesticides (Fig. 1). encountered as pathogens and hence together with key landmarks in our some researchers have referred to understanding of Burkholderia are Burkholderia bacteria are diverse! them as the environmental or beneficial shown (Fig. 1). Here we expand on how The evolutionary history of Burkholderia group. But this is an oversimplification the dilemma of inherent Burkholderia bacteria continues to be unravelled with as certain Paraburkholderia species pathogenicity initially led to a decline the ongoing discovery of novel species can cause opportunistic human in the exploitation of these bacteria as and regular updates to the taxonomic infections, nearly all Burkholderia and beneficial biopesticides in the 1990s. distinction between genera. From their Paraburkholderia occur widely in the

170 Microbiology Today Nov 19 | microbiologysociety.org genus

P. cepacia Burkholderia Pseudomonas cepacia proposed genome completed complex group defined antibiotic screening begins in Cardiff ’ reclassified within new complex third repliconParaburkholderia deletion achieved Discovery of the antibiotic cepacinP. cepacia Cepacin is a key biopesticidal William Burkholder‘cepacia describes syndrome’ Person-to-person in people‘ with transmission CF Burkholderia of cepaciaUS Risk assessmentBurkholderia and biopesticide cenocepaciaBurkholderia moratoriumUnique enacyloxinB. cepacia antibiotic biosynthesisNew genus describedNovel antibiotic gladiolinantibiotic 1952 1984 1990 1992 1997 1999 2003 2007 2009 2012 2014 2017 2019

Spread of epidemic strains in people with CF Burkholderia infection in CF reduced by good infection control

Multiple biopesticidal properties Reduced interest in Renewed interest in Burkholderia as a novel source discovered and commercial use beneficialBurkholderia of antibiotic and specialised metabolites

Fig. 1. Key events in our understanding of Burkholderia bacteria as both pathogens and beneficial bacteria. A basic timeline from the discovery of these bacteria to current research on how they work as biopesticides is shown. Eshwar Mahenthiralingam and Alex Mullins natural environment, and finally, Large unusual genomes and a 1), it was found that the Burkholderia multiple beneficial interactions have non-essential third replicon cepacia complex third replicon was not been characterised for both groups. Given their functional diversity, it is not an essential piece of DNA and could surprising that Burkholderia also have be genetically removed. Third replicon Burkholderia produce multiple very large genomes to encode these mutants lost a number of functions, specialised metabolites multiple capabilities. Their genomes including the production of antifungals The ability to antagonise and kill a are nearly twice the size of most and, most strikingly, their virulence in a range of other micro-organisms was bacteria, ranging from six to nine million range of infection models. a key feature that drove the initial base-pairs of DNA. Burkholderia also exploitation of Burkholderia bacteria represent a minority of bacteria that Burkholderia biopesticides as biopesticides. Although a number package their genomes into multiple Multiple chemically synthesised of antibiotics such as cepacin (Fig. 1) large replicons instead of having just one pesticides are used to protect crops were historically known to be produced chromosomal piece of DNA. The majority against a range of pathogens and during by Burkholderia, recent genomic of Burkholderia and Paraburkholderia vulnerable stages of their growth. analysis has shown that they encode species have two-replicon genome Germinating crop plants are highly prone multiple biosynthetic gene clusters for structures. The Burkholderia cepacia to attack by pathogens, with damping- the production of various specialised complex group of species (Fig. 2) have off disease (the failure of seeds to metabolites. Burkholderia can produce a three-replicon genome. In 2012 (Fig. germinate or rapid wilting of recently polyketide antibiotics (e.g. enacyloxin and gladiolin; Fig. 1) that are made by large, Burkholderia cepacia complex group Burkholderia pseudomallei group modular biosynthetic gene clusters. • More than 20 species • Tropical disease melioidosis They can also make both ribosomally • B. multivorans & B. cenocepacia prevalent in CF • Burkholderia mallei causes glanders in horses synthesised and post-translationally • Commercially exploited as biopesticides • Potential bioterrorism agents modified peptides (e.g. capastruin) and non-ribosomally synthesised Burkholderia gladioli group New Paraburkholderia group peptides and lipopeptide antibiotics • Includes B. glumae & B. plantarii • Mainly environmental (e.g. icosalides). The use of genome • Cause multiple plant diseases including • Certain species can cause opportunistic infection mining to identify novel biosynthetic mushroom rot and rice blight • e.g. Paraburkholderia fungorum gene clusters combined with sensitive analytical chemistry greatly enhances Fig. 2. Example species and the properties of different groups of Burkholderia bacteria. The four groups specialised metabolite discovery in of Burkholderia currently being studied by researchers and example species within them are shown. Burkholderia bacteria. Eshwar Mahenthiralingam and Alex Mullins

Microbiology Today Nov 19 | microbiologysociety.org 171 emerged seedlings) caused by a range of fungi and fungal-like organisms called oomycetes. During the 1990s, several Burkholderia biological control products were registered with the US Environmental Protection Agency (EPA) and used successfully in a range of applications, including protection against damping-off disease. Fig. 3. The antimicrobial activity of Burkholderia ambifaria. Antagonism against the Gram-negative Products, including Deny® and Blue Pectobacterium is shown as a zone of clearing around a black, antibiotic-producing Burkholderia colony (left) Circle® manufactured by Stine Microbial and inhibition of the filmentous growth of the oomycete damping-off pathogenPythium by 3 Burkholderia Products, were described as containing colonies (right). Alex Mullins [Burkholderia cepacia] strains M54 and metabolite biosynthetic gene clusters by Pythium. Simply coating pea seeds J82. These strains and multiple other were encoded and expressed by with the Burkholderia ambifaria enabled isolates with biocontrol properties were biopesticidal Burkholderia ambifaria protection when they were planted in subsequently identified as the species strains. We found that Burkholderia pathogen infested soil (Fig. 4). When the Burkholderia ambifaria. In parallel with ambifaria strains encoded at least same biocontrol assay was carried out this beneficial use as biopesticides, 38 different specialised metabolite with the Burkholderia ambifaria cepacin [Burkholderia cepacia] bacteria were also biosynthesis gene clusters and had a mutant protection was lost. We also emerging as devastating CF pathogens broad range of antimicrobial activity generated a Burkholderia ambifaria third (Fig. 1). In 1999, after assessing the (Fig. 3). We also identified a novel gene replicon mutant which, despite the loss risks of Burkholderia biopesticides, cluster controlled by the bacterial of nearly 1 million bases of DNA, still a moratorium was placed on the signalling system quorum sensing that, had a functional cepacin biosynthesis registration of all new biopesticides until when mutated, stopped Burkholderia gene cluster. The third replicon mutant they could be proven safe (Fig. 1). ambifaria from producing the historical still gave excellent biocontrol protection antibiotic cepacin. of peas but crucially when tested in a Cepacin is a key biopesticidal The Burkholderia ambifaria mammalian infection model it had lost Burkholderia metabolite biopesticidal strains had been shown its pathogenicity and ability to persist. In 2015 we began a genome mining to protect crop plants such as peas study to find out which specialised against damping-off disease caused Future perspectives – what is needed to allow safe use of Burkholderia as biopesticides? It is now clear that Burkholderia represent a novel source of antibiotics and encode a huge diversity of specialised metabolite biosynthetic gene clusters. To fully harness the potential of Burkholderia as natural biopesticides, we have to find out exactly how they work, for example as we have done by uniquely linking cepacin Fig. 4. Biopesticidal protection of peas by Burkholderia ambifaria in soil infested with Pythium. Pea seeds production to protection against Pythium were planted in soil infested with the damping-off pathogenPythium and as a result failed to germinate (left), damping-off disease. We also must coated with Burkholderia and germinated successfully when planted in the same infested soil due to protection find out what happens to biocontrol from antimicrobial cepacin production (centre), and planted in un-infested soil where they germinated strains when they are applied to crops successfully (right). Alex Mullins and left in the field environment. To

172 Microbiology Today Nov 19 | microbiologysociety.org be environmentally safe they need to the chemistry and biosynthesis of Genome mining identifies cepacin as decline naturally, and not build up or Burkholderia natural products. a plant-protective metabolite of the interfere with other microbial systems biopesticidal bacterium Burkholderia that maintain soil health. Further reading ambifaria. Nat Microbiol 2019;4:996– Most importantly we need to make Mullins AJ, Murray JAH, Bull MJ, et al. 1005. sure any Burkholderia biopesticides will be safe for use and will not cause Alex J. Mullins infection. This can be done via an Microbiomes, Microbes and Informatics Group, attenuation strategy; for example, Organisms and Environment Division, School of removing the third replicon greatly Biosciences, Cardiff University, Cardiff CF10 3AX, UK reduced Burkholderia ambifaria e [email protected] pathogenicity, and now with modern Alex J. Mullins graduated from Cardiff in 2015 with a strategies to develop safe bacterial Mullins J. Alex BSc in microbiology, having written his dissertation on vaccines, we can also consider Burkholderia bacteria in the Mahenthiralingam Lab. He decided to pursue this removing other infection-mediating research further and started a PhD, investigating the genomic and antibiotic genes from biocontrol strains. properties of the historical biopesticide Burkholderia ambifaria. Following his PhD, Commercial confidence in the potential he continues to research Burkholderia as a postdoctoral researcher. of Burkholderia biopesticides also appears to be re-emerging in the Eshwar Mahenthiralingam US, with Marrone Bio Innovations® Microbiomes, Microbes and Informatics Group, marketing heat-killed Burkholderia Organisms and Environment Division, School of products possessing nematocidal and Biosciences, Cardiff University, Cardiff CF10 3AX, UK mitocidal properties. Overall, producing e [email protected] enough food to feed the growing human After completing a degree in Applied Biology at Cardiff population is a major global challenge, Mahenthiralingam Eshwar and a PhD with the Medical Research Council, Eshwar and this needs to be balanced against Mahenthiralingam carried out 10 years of postdoctoral research on cystic the environmental impacts of intensive fibrosis at the University of British Columbia, Canada. He joined Cardiff University agriculture. Burkholderia and other in 1999. In addition to teaching microbiology and guiding his research group, he natural microbial biopesticides, which is also Co-Director of Research and works on the school’s management team. will not impact the environment, have huge potential to help sustain future What inspired you to become a microbiologist? agricultural production. Alex: I became interested in microbiology at school when we learnt about major historical diseases such as bubonic plaque and the role of microbes Acknowledgements in vital nutrient cycles such as nitrogen fixation. I saw so much potential in Alex J. Mullins was funded by a these organisms that you could not see and, inspired by a biology teacher Biotechnology and Biological Sciences with a degree in microbiology, I followed up by studying and now researching Research Council (BBSRC) South West microbiology at university. doctoral training partnership (BB/ What skills are required in your position on a day to day basis? M009122/1). Alex J. Mullins and Eshwar Eshwar: When I was training as a microbiologist, the key skill areas I developed Mahenthiralingam acknowledge current were in molecular biology and genomic analyses, and these, combined with funding of their biopesticide research by bioinformatic knowledge, are now crucial for many areas of microbiology. the BBSRC (award BB/S007652/1). We Other key research skills include perseverance, curiosity, and the confidence are also grateful to Professor Greg L. to take risks and occasionally do ‘whacky’ experiments, many of which layed Challis and his research group (University the foundations for successful programmes such as our current Burkholderia of Warwick, Coventry, UK), for their antibiotic discovery research. continuing collaboration to understand

Microbiology Today Nov 19 | microbiologysociety.org 173 FotografiaBasica/iStock

MR is associated with both healthcare and community- Antimicrobial Aproduced factors. One problem is the poorly regulated and poorly enforced use of antibiotics in agriculture and human healthcare in resistance, many low- or middle-income countries causing bacteria to become resistant. One would suspect overuse as key to AMR, but lack of compliance with antimicrobial recommended dosages and duration of therapy are also components as shown for instance in multi-drug- resistant tuberculosis (Mycobacterium peptides tuberculosis). Another community- produced factor is the contact between humans and animals. Recent studies and drug in Africa show how differences in the interaction with husbandry strongly influence microbial resistance patterns in human populations, even when repurposing antimicrobial medication is not a part of the equation. Community-produced AMR factors are certainly key to the future use of antibiotics, as they are by far Thomas Vorup-Jensen, Stig Hill Christiansen and J. Eskild Petersen quantitatively dominating.

Antimicrobial resistance (AMR) defines the ability of a microbe The effectiveness of antibiotics to resist a medicine, which once could be effectively used for The induction of AMR in patients its treatment. This situation is emerging as a major problem receiving regular treatment with broad- spectrum antibiotics is exemplified in in healthcare globally. A closer look at the recent literature, cystic fibrosis (CF). CF is a rare, inherited in particular with a clinical microbiology perspective in mind, disease, which affects the epithelium lining in several organs, including the quickly points to AMR as multifaceted in origins, and hence, not respiratory system. CF patients suffer repeated lung infections, especially a single problem. This has consequences for how to approach with Pseudomonas and Burkholderia the treatment of infections and especially how and when to species. According to data from the UK Cystic Fibrosis Survey, the median focus on new drug therapies. expectation of life for a CF patient for the years 2000–2003 averaged around

174 Microbiology Today Nov 19 | microbiologysociety.org 40 years, and projections suggest a which is now licensed in many peptidic co-polymers, each on average rise to 50 years for the birth cohort countries. However, introduction of 50 residues long and with residues of of the year 2000. This owes much to new antibiotics in human infectious glutamate, lysine, alanine or tyrosine. better and more therapy options. Even diseases will not solve the AMR problem In principle, this permits the formation so, the effectiveness of important unless it is followed up by enforcement of more than 1030 different co- antibiotics, such as the carbapenems of restrictions for veterinary use, polymers. The amino acid composition and aminoglycosides, is reduced by AMR rigorous antibiotics stewardship and was regulated to mimic biochemical in Gram-negative bacteria. hospital infection control – a One Health properties of myelin basic protein, In recent years, the polymyxins, approach. a membrane-associated protein in most particularly colistin, have made the lipid sheath of neural axons and a comeback, still showing in vitro New applications for existing presumably one of the autoantigens in activity against carbapenems and medicines MS. As suggested by the name, myelin aminoglycoside-resistant Gram-negative Drug repurposing is the process of using basic protein carries a high positive bacteria. Polymyxins belong to the class a known drug for new indications. Unlike charge, which, in turn, is also a hallmark of polypeptide antibiotics and essentially simple ‘off-label’ use, drug repurposing of GA, but also a known property of many work by breaking up the bacterial cell involves a systematic evaluation of antimicrobial peptides (AMPs). With an membrane. Colistin, or polymyxin E, was the safety profile of drug candidates additional hydrophobic character, leading originally introduced for human use in and also often a new formulation of to self-oligomerization, GA resembles 1959, but was largely shelved in the the pharmacological active ingredient. the biochemistry of AMPs. With these 1980s due to toxicity issues, primarily The recorded application of an older observations as basis for our hypothesis, kidney failure. The re-introduction to drug provides knowledge of the we tested the antimicrobial activity treat AMR has been particularly useful pharmacodynamics, which make it towards Pseudomonas of the plain GA in CF lung infections where the drug can possible to spare elaborate safety formulation. Much to our surprise, GA be inhaled, limiting systemic side effects. trials for new applications. Thereby, surpassed the activity of the human This makes CF patients an obvious development costs are lowered cathelicidin-fragment LL-37 in 100% target group for new antibiotics that can compared to more standard drug human plasma. The extraordinary be inhaled. development. Drug repurposing heterogeneity of GA has been one of New drugs against the can involve large-scale screening the conundrums in understanding its Gram-positive meticillin-resistant programmes, but such an approach pharmacological mode of action in MS. Staphylococcus aureus (MRSA), including makes the availability of vast drug But as an antimicrobial formulation, linezolid, clindamycin, daptomycin and libraries a requirement. there is a relevant comparison among telavancin, have been brought to the Recently, we published a study naturally occurring AMPs, namely the market over the past decades. The demonstrating that the multiple group of temporins secreted in the latest introduction of new antibiotics sclerosis (MS) drug glatiramer acetate mucus of the European red frog, Rana also effective against Gram-negatives (GA, or Copaxone™) also has an anti- temporaria. Direct investigations showed was the quinolones at the beginning bacterial effect, especially against that temporins together created synergy. of the 1980s and the carbapenems Gram-negative bacteria. It is beyond With ten forms originally identified in at the end of the 1980s. The newest the scope of the present account to Rana, the heterogeneity of the temporins development is the combination of bring forward the complex origins of is far less than for the GA co-polymers, carbapenems, including cephalosporins, this drug; however, in the late 1990s, but this natural defence mechanism with carbapenemase inhibitors (for GA was a landslide in the treatment encourages the speculation that the instance ceftazidime/avibactam), of MS. GA is a composition of random antimicrobial activity of GA originates

Microbiology Today Nov 19 | microbiologysociety.org 175 (a) (b)

Electron microscopy micrograph of Pseudomonas aeruginosa as (a) untreated and (b) treated with GA. Note the formation of intracellular aggregates, which may be part of the antimicrobial effects. Bars, 500 nm.Stig Hill Christiansen

through similar mechanisms as for the new antibiotics are hardly a solution to Further reading synergetic temporins. the AMR problem in its widest sense, Caudell MA, Mair C, Subbiah M, Matthews Our work to provide antimicrobial while the treatment of the relatively L, Quinlan RJ et al. Identification of risk CF inhalation therapy brings into small group of CF patients infected with factors associated with carriage of resistant focus which part of the AMR problem AMR bacteria has some hope in the Escherichia coli in three culturally diverse is solvable by the application of new benefits from the availability of more ethnic groups in Tanzania: a biological and antibiotics. We reported that clinically antibiotics. socioeconomic analysis. Lancet Planet Health isolated Pseudomonas strains with multi- To our knowledge, the current use or 2018;2:e489–e497. resistance to classic antibiotics were developments of AMPs as antimicrobials Christiansen SH, Murphy RA, killed by GA. In terms of the significance is limited to topical applications including Juul-Madsen K, Fredborg M, Lykke M et al. The of new antibiotics development and inhalation. There is little doubt from immunomodulatory drug glatiramer acetate is AMR, we find it necessary to point out numerous scientific studies that AMPs also an effective antimicrobial agent that kills that CF-related AMR and community- hold a broader promise. If the clinical Gram-negative bacteria. Sci Rep 2017;7:15653. produced AMR are different challenges application of AMPs is hindered by Dodge JA, Lewis PA, Stanton M, Wilsher J. when the social setting is included. developing costs, drug repurposing could Cystic fibrosis mortality and survival in the UK: Community-produced AMR is often be a way forward, as we have tried to 1947–2003. Eur Respir J 2007;29:522–526. caused by ill-informed overuse or ad highlight here. The surprising finding of Jalilian B, Einarsson HB, Vorup-Jensen T. hoc interactions with husbandry and its the antimicrobial activity of GA seems to Glatiramer acetate in treatment of multiple products. Directly opposite, AMR in CF suggest a way forward with hypothesis- sclerosis: a toolbox of random co-polymers for emerges from a well-defined clinical driven investigations of older drugs. This targeting inflammatory mechanisms of both need to use intensive antibiotic therapy should inspire more investigations along the innate and adaptive immune system? Int J in critical care facilities. This implies that the route of drug repurposing. Mol Sci 2012;13:14579–14605.

176 Microbiology Today Nov 19 | microbiologysociety.org Thomas Vorup-Jensen What parts of your job do you find most challenging? Biophysical Immunology Thomas: I very much like working in an interdisciplinary Laboratory, Dept. of Biomedicine, environment, where several scientific disciplines work Aarhus University, Aarhus, together to solve questions in immunology or medical Denmark; microbiology. To run a project involving several very Aarhus University Network for different professional backgrounds is challenging,

Thomas Vorup-Jensen Interdisciplinary Drug Resistance especially when findings made by one group of people Research, Denmark; Interdisciplinary Nanoscience Center needs explanation by another group. Likewise, when a (iNANO), Aarhus University, Denmark paper is written up, merging the scientific vocabulary of e [email protected] several disciplines into one coherent text is part of this Thomas Vorup-Jensen, PhD DMSc, is Professor challenge. of Biophysical Immunology with a focus on the Stig: The most challenging part of my job is the occasional pharmacological-mode-of-action of protein-based anti- need to change perspective when working with scientific inflammatory drugs. He has also contributed to the scientific problems. understanding of the innate immune system, notably the Eskild: It is a challenge but also very rewarding to work complement system, with a focus on the biochemistry of with specialists with different backgrounds and assemble integrin complement receptors. a team focused on a research issue. In the complex research environment of today, where everyone is very Stig Hill Christiansen sub-specialised this is where new results and insights are Biophysical Immunology generated. Laboratory, Dept. of Biomedicine, What inspired you to become a microbiologist? Aarhus University, Aarhus, Denmark Thomas: I am an immunologist trying to relate the structure Stig Hill Christiansen, PhD, of proteins to their function in the immune system. Some

Stig Hill Christiansen Stig Hill currently holds a postdoctoral of our work touches upon how the architecture of microbial fellowship at the University of Southern Denmark. Dr surfaces has impacted the structure of proteins, and how Christiansen has a particular interest in innate immunology, our bodies use this as a defence against microbes. It is an but as science has indeed become more multidisciplinary, awe-inspiring revelation to discover the structural logic of his interests today range from immunology, through protein these molecular mechanisms. chemistry, to microbiology. Stig: In fact, I do not consider myself a microbiologist, but more an immunologist. My research spans a broad range J. Eskild Petersen of topics, focusing largely on innate immunology, but since Aarhus University Network for my first microbiology lesson, I have been fascinated by Interdisciplinary Drug Resistance infectious diseases and the micro-organisms that cause Research, Denmark; them. I am particularly interested in antimicrobial peptides Dept. of Clinical Medicine, Aarhus and how bacteria use various resistance strategies to avoid University, Aarhus, Denmark; antimicrobial peptide killing.

J. Eskild Petersen Eskild Petersen J. Dept. of Infectious Diseases, The Eskild: Microbiology is a key specialty between clinical Royal Hospital, Muscat, Sultanate of Oman science and basic cellular science. The molecular J. Eskild Petersen, MD DSc, is Professor of Tropical revolution over the past thirty years has given us great Medicine. His scientific work has focused on toxoplasmosis insight into the functions of bacteria and not least the and malaria. As a clinical specialist and consultant in complicated mechanisms involved in antibiotic resistance. infectious diseases, he has worked in Europe, Africa and the This can have direct clinical implications for the treatment Middle East. He has also focused on treatment of infections of patients and the epidemiology of resistant micro- in adult cystic fibrosis patients. organisms.

Microbiology Today Nov 19 | microbiologysociety.org 177 Annual Conference 2020 #Microbio20 Monday 30 March–Friday 3 April 2020 Edinburgh International Conference Centre (EICC), UK The Microbiology Society will celebrate its 75th anniversary in 2020. To celebrate this milestone, the organisation’s flagship Annual Conference will – for one time only – be extended to five days and will take place in Edinburgh between Monday 30 March and Friday 3 April 2020. Monday 30 March 2020

This prestigious meeting will be held at Edinburgh Edinburgh International Conference Centre (EICC), UK International Conference Centre (EICC) and will include On the first day of Annual Conference 2020, the Microbiology an additional first day (Monday) dedicated to the theme Society will be hosting a special day-long series of Fleming of Alexander Fleming and including a series of high- Lectures organised by an appointed committee of previous profile Fleming Lectures. Fleming Prize winners, chaired by Nobel Prize winner Sir Paul This will be followed by the standard four days Nurse. (Tuesday, Wednesday, Thursday and Friday) of scientific Compèred by Alice Roberts (University of Birmingham, UK) sessions. As ever, these sessions are designed to and with a keynote from Bonnie Bassler (Princeton University, demonstrate the impact and potential of microbiology USA), the day will offer an opportunity to hear the legacy of some to address important global challenges. of the past Fleming Prize winners and will focus on the influence of both established and up-and-coming scientists in addressing global challenges. The day will feature presentations from a global speaker line- up, including: • Luke Alphey, Pirbright Institute, UK – Genetic control of mosquitoes • Liz Sockett, University of Nottingham, UK – Predatory Bdellovibrio bacteria – 58 years of understanding them as allies against AMR infections • Grant Jensen, CalTech, USA – Visualizing bacterial nanomachines in situ by electron cryotomography • Eddie Holmes, University of Sydney, Australia – The expanding virosphere • Mark Pallen, Quadram Institute, UK – Palaeomicrobiology: what ancient DNA can tell us about pathogens from the past • Stirling Churchman, Harvard University, USA – Orchestrating gene regulation across the genome and across the cell Early career microbiologists can attend the Fleming Showcase day for free when registering for Annual Conference 2020. Further information about the day can be found on our website (microbiologysociety.org/microbio20). EICC

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@MicrobioSoc rabbit75_ist/Thinkstock Destination Edinburgh provides an excellent platform for The Real Mary King’s Close will be Edinburgh is a diverse and vibrant city, emerging scientific research. Posters opened up exclusively for registered steeped in history. The backdrop of will be rotated to ensure relevance Society delegates. On Thursday evening Arthur’s Seat, the Pentland Hills and to the content of the day’s live (2 April 2020), the ever-popular Annual Edinburgh’s waterfront make the city an programmed sessions. See the website Conference Quiz will be taking place exciting event destination. If you extend (microbiologysociety.org/microbio20) at Ghillie Dhu – a dramatically vaulted your stay after Conference, there are for further information and submission Georgian converted church in the plenty of attractions to visit, such as categories. shadow of Edinburgh castle. Edinburgh Castle, the National Museum Prices, times and further details of Scotland, the Scottish Parliament and Early career microbiologists about all socials can be found on the the Royal Yacht Britannia. Visit ‘This is Annual Conference has many event website. Edinburgh’ (edinburgh.org) for further opportunities for early career information. microbiologist members to get involved. Grants If you’re eligible, don’t forget to indicate Society Conference Grants are available Registration your interest in participating in the Sir to support eligible members wishing to Registration is now open for Annual Howard Dalton Young Microbiologist of present at the Annual Conference. The Conference, which attracts over 1,600 the Year Competition, and/or the Early grants deadline is 20 January 2020. attendees for the UK’s largest annual Career Microbiologists’ Forum Co- Grant notifications will go out before gathering of microbiologists. chairing scheme. 31 January 2020. Full information is To ensure the meeting remains available on the Society Conference of value for this broad microbiology Conference programme Grant page (microbiologysociety. community, ticket prices have not Annual Conference 2020 has over org/societyconferencegrants). If you increased from last year beyond the rate 30 scientific sessions, covering topics are a member who is not eligible for of inflation. A 10% discount is available across the breadth of microbiology, a Society Conference Grant, please for anyone registering for all four days of and workshops, forums and symposia apply via the Travel Grant scheme: the meeting and registered early career specifically aimed to help with (microbiologysociety.org/travelgrants). microbiologists can attend the Fleming professional development and Showcase for free. cross-disciplinary learning. You can view Accommodation and travel Further information can be found the current 2020 programme online, If you’re planning on joining us at this on the event page of the website including a list of the invited speakers important event, we highly recommend (microbiologysociety.org/microbio20). and their talk titles and abstracts. you secure your accommodation and make your travel plans as early Abstracts Social programme as possible. Edinburgh is a popular Abstract submission is now open and Annual Conference is designed to offer destination city and hotels fill up quickly. submission information is on the website. ample opportunities for formal and To support you in securing your As always, Annual Conference informal networking for both early accommodation, you can book through is designed to cover the breadth of career and established microbiologists. our booking and accommodation microbiology research, so don’t miss Two low-cost, separately bookable services agent Reservation Highway out on this opportunity to showcase events are taking place as part of the (reservation-highway.co.uk/micro20). your microbiological work and research social programme in 2020. The agency has secured a range of to this broad scientific community. On the Tuesday evening (31 March accommodation options to suit all Submissions close on 9 December 2019. 2020) of Annual Conference week , budgets throughout Edinburgh, at Notifications of acceptances will VisitScotland’s five-star-rated attraction discounted rates. be made from 14 January 2020. To get the latest Annual Conference news and updates, follow us on Twitter For those abstracts that are awarded @MicrobioSoc using the hashtag #Microbio20. a poster presentation, Annual Conference

Microbiology Today Nov 19 | microbiologysociety.org 179 Focused Meetings 2019and Events update The conferences and events team delivered five successful Focused Meetings throughout the year, rounding off the 2019 programme. The Focused Meetings are key events in the Society’s calendar, presenting opportunities for microbiologists with shared interests to explore new scientific research, form new connections and hear from a varied line-up of distinguished invited speakers. Anaerobe 2019: Changing perceptions of anaerobic bacteria; from pathogen to the normal microbiota and back 13–14 June 2019 | Jurys Inn Cardiff, UK Our first Focused Meeting of the year took place in Cardiff and was organised in collaboration with the Society for Anaerobic Microbiology and Welsh Microbiological Association. The meeting was very well received, as it provided scientific insights into the future impact of anaerobic bacteria in human health and disease, addressing the implications of recent microbiota studies as well as the continued threat of emerging and re-emerging anaerobic infection.

British Yeast Group 2019: Discovery to Impact 26–28 June 2019 | County Hotel, Newcastle, UK The Microbiology Society was pleased to once again incorporate the ‘BYG’ meeting into its Focused Meeting programme this year, bringing together members of the British Yeast Community at this long- standing annual event. Over 70 delegates from throughout the UK and beyond enjoyed three days of fantastic science, exploring the theme of Discovery to Impact. The meeting also featured a varied social programme, offering delegates plenty of opportunities to make new connections, discuss research projects and strengthen relationships in the scientific community.

IMAV 2019: International Meeting on Arboviruses and their Vectors 5–6 September 2019 | University of Glasgow, UK The third IMAV: International Meeting on Arboviruses and their Vectors took place in Glasgow in September and proved again to be a great success. This series of meetings is getting stronger and stronger and becoming a must-attend event for the arbovirus research community. We look forward to the next meeting in 2021.

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Microbes in Medicine: A Century of Microbiology at Trinity College Dublin 24–25 October 2019 | Trinity College Dublin, Ireland In 2019 the discipline of microbiology celebrated its centenary year and we marked the occasion at the penultimate Focused Meeting of our 2019 programme. The meeting, at Trinity College Dublin, brought together scientists and medical practitioners with an interest in the use of microbes and microbial products to treat and prevent diseases to hear a range of fascinating talks from renowned invited speakers and early career researchers. The Society was pleased to incorporate a special presentation from session organiser, ock /iSt Charles Dorman, who delivered the prestigious Trinity College Dublin Inaugural teur chan Lecture to meeting delegates and a range of invited guests. Marc Le

Antimicrobial drug discovery from traditional and historical medicine 29 October 2019 | Ashmolean Museum, Oxford, UK Great networking opportunities were created at the Focused Meeting: Antimicrobial drug discovery from traditional and historical medicine in Oxford. This new format meeting has been very positively welcomed by attendees and helped to build new effective networks for researches from a range of fields including microbiology, Ryan King99/iStock chemistry, botany and the history of medicine.

Focused Meetings 2020 Call for Annual Conference Sessions Proposals Our 2020 Focused Meeting programme The deadline to send your session ideas for our Annual Conference 2021 is is now online – visit our website 16 December 2019. We welcome session suggestions from members (microbiologysociety.org/events) for the working in any field of microbiology. If you have an idea for a session and most up-to-date information. Don’t forget would like it to be considered by our Divisions at our next conferences and that our Scientific Conferences Committee is events planning day, we want to hear from you. The Divisions meet in January always open to new proposals to become part every year and if your suggestion is accepted, the Scientific Conferences of our future events programme. Committee (SCC) will appoint experienced session organisers to finalise the Why not discuss your ideas with our session programme. Visit our website (microbiologysociety.org/events) to Head of Conferences and Events, Laura Crick download the suggestion form. ([email protected])?

Candida and Candidiasis 2020 – Society-Supported Conference Grants Abstracts open The Microbiology Society provides financial support for events held by Abstract submission is now open for members in all areas of microbiology. The deadline for the next round of Candida and Candidiasis 2020, taking place applications for a Society-Supported Conference Grant is 16 December 2019. in Montreal, Canada, 19–23 April 2020. Members can apply for a grant of up to £2,000 towards covering the costs of The abstract deadline is 9 January 2020. invited speakers, travel and accommodation. More information, including the Further details can be found at eligibility criteria and the application form, can be found on our website at ( ). microbiologysociety.org/candida2020. microbiologysociety.org/ssconferencegrants

Microbiology Today Nov 19 | microbiologysociety.org 181 Annual General Meeting and Showcase of the Society’s Achievements Members at the networking event. Each year the Society hosts Annual Conference, 2018 Irish meeting and 2018 Annual Conference. a showcase event, before our Each finalist gave a fantastic Annual General Meeting, for presentation of their research in another hard-fought competition. The Society early career members of the congratulates all of the finalists and Society to come together, thanks those who took part in the meet each other and learn competition. The winner was then announced at the evening reception. from other members of the Congratulations to Davis Laundon, Society who are further on in from the Marine Biological Association, University of East Anglia, for winning their careers. first prize for his talk ‘Shining new lights on chytrid cell biology: quantitative live Matt Hutchings. he event allows us to recognise cell imaging of rhizoid development in and third-prize winners Sarah Worsley the excellent work our Committee an early-diverging fungus’, and to second and Michaela Conley, respectively. Tmembers, Champions and Prize Davis said of winning the prize: Winners have accomplished over the “The competition was absolutely past year. amazing this year. I thought every This year’s event, which took place presentation was excellent and on 12 September 2019, at The Law incredibly well communicated. To be Society, London, began with a talk from awarded the prize amongst those Dr Lindsay Hall on ‘Building and being presentations was a really huge honour a part of a team’, followed by a series and incredibly flattering.” of networking activities for our early After the business of the AGM, career members which focused on the final celebration of the day was bringing together ideas and how to work Professor Matt Hutching’s Microbiology collaboratively as a team. Outreach Prize talk on his outreach Guests were then invited to view project ‘Antibiotic Hunters’. posters from the Annual Conference Matt explained that the project is poster prize winners during lunch, about “our hunt for antibiotics … and the before the final of the Sir Howard Dalton Davis Laundon and President Professor Judith kind of weird and wonderful places that Young Microbiologist of the Year (YMOY) Armitage. we try and find them”. Competition began. The nine finalists Watch Q&As with both Davis Laundon and Matt Hutchings on our YouTube channel were shortlisted from a range of oral and (microbiologysociety.org/youtube). poster presentations given at the 2019

182 Microbiology Today Nov 19 | microbiologysociety.org Spotlight on grants: Education and Outreach

Education and Outreach Grants support a variety of science teaching and engagement activities, providing members with opportunities to improve microbiology teaching, outreach and communication to many different audiences.

arlier this year, PhD student Sabastine said the project School children aided by volunteers to perform Sabastine Arthur (University of provided “an opportunity to discuss experiments to identify an infectious disease agent in an outbreak incidence. VISA ECambridge, UK) was awarded a the importance of vaccination and grant to support his outreach project, encouragement of personal hygiene in Sabastine said the highlight of his ‘Be aware of Infectious Disease preventing disease outbreak.” project was that it enabled his team to Epidemic’ (BIDE), in Ghana. The aim The programme ran for four “deconstruct the myth that science is of this project was to demonstrate days and over 200 school students a difficult discipline to pursue, and that to school children how an infectious participated. Students were given a short anyone can do science irrespective of disease outbreak can be diagnosed series of lectures and practical sessions their gender, financial background or and managed within a community. The to inform them about common infectious social status.” method of engagement was adopted diseases, such as Ebola and measles, Since returning from Ghana, the from Dr Lucy Thorne (University and how we can identify them. They also project has developed so that it can be College London, UK) and Professor Ian learned how an outbreak may arise and run by Sabastine’s group of volunteers in Goodfellow (University of Cambridge, subsequently how infection can spread different institutions and regions across UK) with whom Sabastine worked with beyond their schools – through homes, Ghana. The team are now planning closely over the course of the project. hospitals and wider communities. to set up a lab that will be involved in Sabastine also worked closely with Students could then apply what engaging children in several practical Ghana-based NGO ‘Vacation Initiatives in they had learnt to a series of incidence science activities in line with the Ghana Science, Africa’ (VISA) and ‘Hardie Wren outbreak case studies. This involved Education Service science curriculum. Development Initiatives’ to organise performing glucose tests on simulated Applications for the Education the project from Ghana and the UK, blood samples and analysing Lego- and Outreach Grants open twice respectively. brick-built sequences of DNA that a year, in January and June, with corresponded to a host of pathogens. deadlines in April and October, To end the programme, a local respectively. To find out more, visit our Post-engagement activity photo of a group of journalist was invited to engage students website (microbiologysociety.org/ volunteers and school children of Labone S.D.A Basic through a series of question and answer educationandoutreachgrants). School, Accra, Ghana. VISA sessions. This enabled them to reflect on To find out more about the wide what they had learnt range of grants available to support and effectively Microbiology Society members, communicate visit the grants area of our website this to a wider (microbiologysociety.org/grants). audience.

Microbiology Today Nov 19 | microbiologysociety.org 183 The new face of Microbiology

Microbiology is the Microbiology Society’s founding and flagship exciting place to publish. ‘Publishing for the community’ is our tagline and this is journal. The journal publishes fundamental and applied research really true – it’s about the microbiology across the breadth of the field of microbiology and supports the and ensuring the future of the Society. exchange of knowledge on key topics such as new and emerging Why have you changed the scope? diseases, antimicrobial resistance, food security, environmental TP: Microbiology has been important since sustainability and health. the beginning of civilisation, from many perspectives. Microbiology has always aimed to cover the widest breadth of e spoke to Tanya Parish, course, I got to continue working with research, reflecting its key role in science Editor-in-Chief of Microbiology, some fantastic colleagues, both on the and society. As new research areas Wand Gavin Thomas, Deputy Editorial Board and in the Society’s develop and old areas change, we need Editor-in-Chief, to outline why Publishing Team. to keep up with these developments. Our Microbiology remains an important scope sets out the journal’s scientific place to publish and how its revised Gavin Thomas (GT): As a member of the vision and provides a home for all those scope will better meet the needs of the Society for almost 20 years now, I have new areas. For example, microbiology microbiology community. benefited massively from its activities will play a key role in delivering the in my career, and so have my PhD and United Nations Sustainable Development Why is Microbiology important, and postdoctoral students. From my first Goals. We have broadened our scope to why are you involved with it? meeting, I was welcomed into the family include newer areas like microbiomes Tanya Parish (TP): Microbiology is the of microbiologists and found the Annual and antimicrobial development, as well flagship journal of the Society, playing Conference as the main way to learn as applied and translational research, a pivotal role in the dissemination of about the best new science and meet but have also tried to simplify the way we information between microbiologists. It the scientists themselves. I got a travel present it, so it is more welcoming. We aims to connect scientific communities grant to enable me to attend this first are looking for articles that advance our and stimulate ideas and new research. meeting; membership for students was knowledge in the broadest sense. Articles I have been associated with the journal cheap and they sent me a magazine should include novel work, be conducted for many years, as an Editor, then with lots of cool articles and news. As I to rigorous methodological and ethical Senior Editor, and finally Editor-in- became a Principal Investigator myself standards, and have sound conclusions. Chief. As a scientist, it is important to and grew my own group, I was delighted me to include activities that benefit to become an Editor for the journal and Why should members publish with other microbiologists – whether that is then later Senior Editor, and it became Microbiology? reviewing papers, discussing methods clear to me how important the journal TP: We have a robust and fair peer and approaches with students at is for running all the other activities of review process, overseen by a world- meetings, or in this case, taking on the Society. The continued success of class Editorial Board; a fast time-to- the responsibility of developing new Microbiology is central to the continued publication for accepted papers; it’s free initiatives with the journal. In addition, I success of the Society. By working with to publish and we have a liberal Open felt it was an important way to ensure our membership who benefit most from Access policy. For Society members, that we address issues of gender the success of Microbiology, we need most importantly, we provide financial representation and diversity. And, of to revitalise the journal to make it an support to other Society activities.

184 Microbiology Today Nov 19 | microbiologysociety.org Publishing for the community microbiologyresearch.org GT: We are making the link between the journal and the Society much clearer to members. We are also starting MICROBIOLOGY new activities to promote the link of mic.microbiologyresearch.org the journal to the community, the first #MicrobioJ of which is the creation of the actinobase.org wiki. JOURNAL OF TP: Members can also get involved GENERAL VIROLOGY by volunteering for the reviewer jgv.microbiologyresearch.org database or putting their name #JGenVirol forward to be considered as an Editor. Suggestions for collections, special issues and/or Focused Meetings are also welcomed. JOURNAL OF MEDICAL MICROBIOLOGY Where do you see the journal in jmm.microbiologyresearch.org five years? #JMedMicro TP: Microbiology as a field is always developing, so we may see new areas being included. The biggest changes MICROBIAL GENOMICS we expect to see are not in terms of mgen.microbiologyresearch.org publications, but in the work we do, #MGen in the broader sense of supporting communities. Over the past five years, we have introduced two new article types, graphical abstracts, a board of INTERNATIONAL JOURNAL OF reviewers and a volunteer reviewer SYSTEMATIC AND EVOLUTIONARY database, as well as poster and speaker MICROBIOLOGY prizes at conferences, and we expect to ijs.microbiologyresearch.org continue introducing new initiatives. #IJSEM

GT: I want to see scientists fully engaged with the journal again and publishing ACCESS MICROBIOLOGY their work there as a matter of choice. acmi.microbiologyresearch.org When you have a solid piece of work you #AccessMicro want to be well reviewed and well read then you should publish in a Society journal to help support our work, rather We hope that you’re finding these articles useful. If there is a topic you than the shareholders of commercial would like us to address, email us at [email protected]. publishers.

Microbiology Today Nov 19 | microbiologysociety.org 185 Reviving the antibiotic research and development pipeline: marine natural products

The growing threat of antimicrobial resistance (AMR) has brought into sharp focus the pressing need for the development of new antibiotics. Already, AMR is estimated to cause at least 700,000 deaths around the world each year.

hat figure is predicted to rise profitable therapeutic ventures. These candidates. They include research to 10 million, alongside a moves are seeing smaller biotech grants, tax incentives and public– Tcumulative cost of $100 trillion, companies occupying the space and private partnerships. Instead of by 2050 if no action is taken. The developing new antibiotics, as well sharing costs, pull mechanisms barriers to bringing new antibiotics to as increasing pressure on public-led increase NPV by guaranteeing or market hinge primarily on the lack of funding to support the development increasing the revenue of a new return on investment. Unlike drugs that of new products. antibiotic. This can be through policies treat the symptoms of chronic disease, In response to this growing crisis, that accelerate the regulatory pathway, antibiotics offer a relatively poor return numerous major international and extend market exclusivity or provide a on investment because they are taken national initiatives aimed at financially direct monetary contribution. The UK for a short period of time and cure their incentivising antibiotics research 5-year action plan for antimicrobial target disease. Moreover, prescribing a and development (R&D) have been resistance (2019–2024) sets out a new new antibiotic is likely to be restricted implemented. Support for R&D can payment model that will reimburse for fear it will become resistant. The be split into two broad categories of pharmaceutical companies based on many market failures and the high cost incentives: push and pull mechanisms. how valuable their drugs are to the of AMR are not currently reflected in Push mechanisms share R&D costs National Health Service (NHS), rather the cost of the drugs. As a result, many across several parties to reduce a than on the quantity of antibiotics large pharmaceutical firms have exited firm’s outlays and to increase the net sold. This UK pilot project will be the the antibiotic space in favour of more present value (NPV) of their antibiotic world’s first delinked pull incentive for

186 Microbiology Today Nov 19 | microbiologysociety.org considered to be excellent sources of novel natural products. Marine natural products could contribute to reviving the antibiotic discovery pipeline, as they are an untapped reserve of potential antibacterial agents. After running the project for only 18 months, the Bristol team had already isolated more than 1,000 previously uncharacterised micro-organisms, and six new natural product-based antibiotic leads. However, Dr Race explains that the lack of funding mechanisms bringing Silk-stocking /iStock academia and industry together is a blocker in realising the potential of antibiotics. The upfront payment with Searching for antibiotics in the abyss what might already be available. He the new model is expected to encourage At the University of Bristol, Dr Paul also points to the O’Neill Report (‘The drug makers to invest the estimated Race and colleagues are combining Review on Antimicrobial Resistance’ £1 billion required to develop a new the innovations of synthetic biology commissioned in 2014 by the UK Prime medication, as they can be reassured with robotic environmental sampling Minister, who asked economist Jim that they will still be paid for the drug to attempt to unblock the antibiotic O’Neill to propose concrete actions even though it may be stored for discovery pipeline. The ‘antibiotics in to tackle the global problem of AMR) reserves. Rebooting the antibiotic R&D the abyss’ discovery team ventures and its numerous suggested solutions pipeline requires global support. For this deep into the ocean, one of the most to circumvent economic barriers and reason, the UK initiative will be evaluated extreme environments on Earth, to expedite antibiotic discovery: “the crux from the start and findings will be find micro-organisms that have been of the problem is that there is a plan but shared with the rest of the world so exposed to evolutionary pressures that nobody to pick up the baton and make that other healthcare systems can test necessitate the acquisition of unusual that plan a reality”, says Dr Race. He also similar models. metabolic innovations and are therefore highlights the need to keep pressing for more investments in all aspects of AMR research, underlining that, “big problems Find out more about Dr Paul Race and the ‘antibiotics in the abyss’ team on require big money” and to develop a their website: microb.io/2AD1TeM. global initiative that would bring together The Microbiology Society published a news story about the UK 5-year AMR those working across the pipeline of strategy and 20-year vision, available on our website: microb.io/2DFC6oB. drug discovery and clinical development: “it is only by working in an integrated Please visit the ‘A Sustainable Future’ page on the website for further details manner and with a significant amount of on how AMR represents a global threat to health and well-being, as well as dedicated resources that we can win the opportunities to contribute to the project: microbiologysociety.org/SDGs. global fight against AMR”.

Microbiology Today Nov 19 | microbiologysociety.org 187 Reflections on being a member of the Microbiology Society

When we ask members why they joined the Society, we get a diverse range of responses. We have members in over 90 countries, ranging from those still studying, through to those who have completed successful careers in academia, research, industry and public service. As we approach our 75th anniversary year, we thought you

might be interested to hear about members’ experiences of being part of our global community.

My first (unsuccessful!) job application in I’ve been a member since 1986, having trained in the 1982 was to the Society, to join the Journal UK, but I have spent most of my working life in the US. “ of General Microbiology (now Microbiology) As a result, I haven’t been able to participate in as team. I became a member in 1983 on many conferences and events as I may have liked to. the advice of my PhD supervisor, Dr Tony However, I very much believe in your mission and want Roberts. to give something back to UK microbiology through the “ I have been a member of multiple “Society. Being a member has enabled me to do that. societies, but the Microbiology Society David Leib has always felt like my professional Geisel School of Medicine, Dartmouth College, USA home. Conferences have been important for maintaining a wide In 1989, as an Australian, medically-qualified student undertaking his PhD microbiological in Cambridge, I joined the Society for General Microbiology (as it was then), perspective, but I also as did many of my fellow students and postdocs. For me it was a way to gained vital early- integrate into a group of like-minded researchers and see, first-hand, the

career committee excellence that was, and is, British science and critical thinking.

and conference The Microbiology Society provided an initial welcome that was

organisation “unconditional, and since then it has been a great journey. The formal

experience. A grant meetings, and informal opportunities to hear, and speak, with senior from the Society enabled virology researchers who had great depth and me to work in the Hancock understanding, meant I saw my work in “ Lab (University of British “ the context of much longer and more Columbia, Canada). So, membership has complex scientific endeavours. That sense provided me with important development of belonging, intelligent discourse and opportunities and enabled me to work and engagement meant a lot early on in my form friendships with many members of the career, and continues to this day, despite time international microbiology community. and distance. Deirdre Devine William Rawlinson School of Dentistry, University of Leeds, UK The Prince of Wales Hospital, Australia

188 Microbiology Today Nov 19 | microbiologysociety.org When I was in the Sixth Form at school there was very little mention of anything to do with microbiology. The emphasis was on a thorough grounding in physics, chemistry and mathematics, and any plant or animal that could be readily seen without the use of a microscope! My degree course “in Biological Chemistry alerted me to the new world of fungi, but bacteriology was only taught to medical

students, apart from a few lectures on legume nitrogen- fixing bacteria. All was to change when I was awarded a Civil Service Commission

Post Doctorate Fellowship on the development of improved vaccines against bubonic and pneumonic plague at the Microbiological Research Establishment, Porton Down. I just had to learn more about microbiology! Joining the Microbiology Society in 1958 enabled me to learn about the “ Joining the Microbiology Society in 2013 latest advances in mycology and bacteriology from the world’s leading was one of the best decisions of my microbiologists, including Professor Harry Smith FRS. life. I was curious to learn more about The integration of microbiology teaching into degree courses in botany microbiology and so I wrote and asked to was made so much easier by the expert guidance of researchers, many of join the Society. I was the first person to whom were members of the Microbiology Society. Many today are still as join the Society from Nepal! Soon, I joined willing as ever to lend a helping hand. “the Champions programme and from Edward Cocking the support of the Society I was able to Emeritus Professor, University of Nottingham, UK organise a variety of events. The Society constantly encouraged me by featuring I came to the Microbiology Society in 2014 as a my work and events on the website and second year PhD student when I attended the in Microbiology Today magazine. This Annual Conference for the first time. The talks also helped me get better were amazing; I remember being hard pressed to recognised within my own choose which ones to listen to and where to go as workplace and among there was so much going on. I was so mesmerised

other organisations “by the experience that I felt I had missed out by too. In 2019, I got a not joining in my first year! As a result, I became an

chance to attend the active member and volunteered to become a Society Annual Conference Champion.

and experience the Membership has brought me so many opportunities and lectures, workshops experiences. I’d say that I love the Annual Conference, Microbiology and opportunities to Today magazine, the outreach activities I have taken part in and the “ meet other members and “ opportunities I’ve had to connect and network with so many other Champions. They could not scientists. Having said that, the single most memorable opportunity for have been more supportive. The Society me was the chance to attend the Parliamentary Links Day, in which the is a great place to share ideas and work future of science after Brexit was being discussed amongst the scientific experiences and has really widened my community and government representatives. It was a real privilege to understanding and perception of the field. be part of this. Manoj Pradhan Marília Costa Nepalese Army Institute of Health Sciences, Nepal Paraíba State University, Brazil

Microbiology Today Nov 19 | microbiologysociety.org 189 Microbiology Society and MiSAC: 50 years of Cutting the celebratory cake to mark the 100th MiSAC committee meeting, July 2008. Right to left: Janet Hurst mutualism (then Secretary) and current officers Margaret Whalley (Treasurer), John Tranter (Secretary), John Grainger (Chairman, centre) and John Schollar (Vice-Chairman, extreme left). MiSAC n the 1960s the major professional to the Microbiology Society staff. Janet Northern Ireland during the first biological societies became aware became MiSAC Secretary in 1991, with decade of the 2000s. Other notable Iof an increased need in schools for support later from Dariel Burdass, a collaborations with MiSAC were the support for the teaching of specialist then new staff colleague who was also a Microbiology Society publications aspects of biology in response to microbiologist. The Microbiology Society Practical Microbiology for Secondary marked changes in curricula brought also undertook administration of the Schools (2002) and Basic Practical about by new developments such as MiSAC Annual Competition and provided Microbiology: A Manual (2003). Nuffield Biology. The response by the space on the Society web server until In recent years, the Microbiology Microbiology Society (then named the MiSAC developed its own website. Society representative on MiSAC was Society for General Microbiology) was to Among the early contributions drawn from Society staff, but is now organise a symposium from which arose made by MiSAC was involvement in again a role open to Society members, a joint committee – the Microbiology in several revisions of the Microbiology with the representative also being Schools Advisory Committee (MiSAC) – Society schools booklet Careers in part of the Society Communications in 1969, consisting of representatives Microbiology. Encouraged by the growth Committee. Rachel Exley was appointed of the Microbiology Society and other in schools’ activities, the Microbiology to the position in 2018 and has quickly organisations with experience of and Society made funds available in 1983 become very involved, including joining interest in school education. for a Schoolteacher Fellow to produce Margaret Whalley, MiSAC colleague and Following my appointment as the practical activities, in a project directed a member of the British Mycological Microbiology Society representative on by MiSAC to which Paul Wymer was Society, as co-editor of MiSAC matters: MiSAC in 1973, the associated activities appointed to work with me in the 50th Anniversary Articles (misac.org.uk). between the two organisations began to Department of Microbiology at Reading Several Microbiology Society members flourish. I held the role as Microbiology University. The major outcome of have contributed to this celebratory Society representative until 1994, having the project, the publication Practical publication, including Sir Paul Nurse and become Chairman of MiSAC in 1983. Over Microbiology and Biotechnology for President Professor Judith Armitage. this time, the activities of MiSAC were Schools, led the then Department of This year MiSAC celebrates its 50th markedly reinforced by the appointment Trade and Industry to provide funds in anniversary. The close coincidence with of Janet Hurst, a microbiologist with 1985 to establish the National Centre Microbiology Society’s 75th anniversary administration and writing experience, for Biotechnology Education (NCBE) at next year is well worth recording, Reading, where it still operates. With because of both the key role that the MiSAC sponsors support from MiSAC and NCBE, the Microbiology Society played in the British Mycological Society: britmycolsoc.org.uk Microbiology Society also developed formation of MiSAC in 1969, and the CLEAPSS: cleapss.org.uk practical courses for teachers, many ways in which a long-lasting and Microbiology Society: microbiologysociety.org technicians and postgraduate certificate close association developed between the National Centre for Biotechnology Education: of education (PGCE) students. These two organisations to support the future of www.ncbe.reading.ac.uk became a significant activity whereby microbiology. Quekett Microscopical Club: quekett.org John Schollar of NCBE and myself Scottish Schools Education Research Centre: delivered some 100 such courses John Grainger sserc.org.uk throughout England, Wales and [email protected]

190 Microbiology Today Nov 19 | microbiologysociety.org Early Career Microbiologists’ Forum Update: Looking forward: translating research and tackling mental health

I can’t believe that this is my the Communications Representative position was open for nominations, I Is there anything else you would like last Microbiology Today ECM knew I had to go for it. I got the bug to add before I hand over the reins? Forum update! The Executive for science communication from my I wanted to say thank you to you tutor at Swansea, Dr Dan Forman, who Rebecca, for all that you have done Committee was brand new is one of those people that can make over the past few years as Comms when I joined, and it has been science interesting and fun to anyone! Rep! I would also like to mention Discussing the role with you, Rebecca, the Microbiology Society Champions a privilege to see the Forum and the current and former Chairs of the again; if you’re interested, Paul Easton grow over these three years. Forum made me really want to represent ([email protected]), early career microbiologists. Head of Membership Services at the Society, can give you more information. our new Communications What do you hope to achieve over your Finally, thank you so much for all those Representative will be Robert term? who voted for me; I really appreciate it YWill, a second year PhD student The big thing I have found during my and I hope I live up to the trust you put at the University of Cambridge, under time as a student is how difficult it can in me! the supervision of Gordon Dougan be to decipher science without pre- and Ankur Mutreja. He is investigating existing knowledge. My main aim is to Robert will officially begin his term in the global evolution and diversity of promote how amazing microbiology January, so if you have any questions or Corynebacterium diphtheriae. I spoke and the Society are, by looking at how suggestions for him then please do get to Robert about the motivation behind we can increase opportunities for in touch. Good luck Robert! running for the Executive Committee ECMs to get involved with microbiology and his hopes for his term. communication. Visit our website My other aim is to work with my (microbiologysociety.org/champions) Congratulations on your election! fellow ECM Forum Committee members to find out more about the Society Why did you decide to run for the to aid the Society in its efforts to support Champions scheme. Communications Representative the mental health of ECMs. This is an position? important and well-documented issue Rebecca Hall I was already a Microbiology Society for postgraduate students and we Communications Representative, Champion and was looking at ways can build on the information already ECM Forum Executive Committee to get more involved. When I saw that available at the Society.

Microbiology Today Nov 19 | microbiologysociety.org 191 Member Q&A

This is a regular column to introduce our members. In this issue, we’re pleased to introduce Zina Alfahl.

Where are you currently based? Where did your interest in I am currently based in the United microbiology come from? Kingdom and am studying for a PhD My interest in microbiology started in at the School of Pharmacy, Queen’s the second year of my undergraduate University Belfast. degree, when I discovered that microbiology has a huge impact on our What is your area of specialism? lives. I was keen to explore and find out My research in microbiology focuses more about microbes in the human body, on the detection of pathogenic bacteria and how microbiology helps us in curing of potential clinical relevance in people many life-threatening diseases. with bronchiectasis. What are the professional And more specifically? challenges that present themselves, There are currently no guidelines for and how do you try to overcome the management of bronchiectasis. My them? Zina Alfahl project focuses on the determination Working in a world-class laboratory What do you do to relax? of the relationship between airway was my dream when I started planning I’m passionate about travelling. microbiome composition, inflammation for my PhD, but at the same time I was Travelling helps to relieve stress. and clinical outcomes in bronchiectasis, aware that I had to commit a large as well as informing the choice of both amount of time and effort, which can be What one record and luxury clinical and lab outcome measures for stressful. I learned how to handle stress item would you take to a desert future clinical trials. This is likely to and how to manage my time to achieve island? help with targeting new therapies in my targets. Moreover, the laboratory A scientific book and my mobile. bronchiectasis. environment I am working in hasn’t hesitated to help me to overcome any Tell us one thing that your work Tell us about your education challenges. colleagues won’t know about you. to date I don’t like complaining and wasting I obtained my first-class honours What is the best part about time. Bachelor of Pharmacy degree from Al ‘doing science’? Ain University of Science and Technology, The best part of ‘doing science’ is the If you weren’t a scientist, United Arab Emirates. I then moved to ability to adopt and develop problem, what would you be? the UK to pursue my higher education solving strategies that can overcome any A lawyer. at Queen’s University Belfast with the obstacles a scientist might encounter. Halo Research Group, which investigates If you would like to be featured in infection in chronic lung disease, and Who is your role model? this section or know someone who the Northern Ireland Clinical Research Any successful person in life I consider may, contact Paul Easton, Head of Facility (NICRF) team under the my role model. I am grateful for Membership Services, at p.easton@ supervision of Professor Michael Tunney everyone in my life and there are many microbiologysociety.org. and Professor Judy Bradley. who inspire me.

192 Microbiology Today Nov 19 | microbiologysociety.org Obituary

common motif present in the PDB. Professor Michael Rossmann More significantly, Michael proposed that proteins were composed of domains, each with a specific function 1930–2019 and conserved structure. This concept is a fundamental principle of protein Professor Michael Rossmann, Hanley Distinguished Professor structure, function and evolution. of Biological Sciences at Purdue University, USA, and recipient The methods Michael developed of the Microbiology Society Prize Medal in 2017. to interpret the non-crystallographic symmetry of dehydrogenses were then n a career spanning over 60 years, of Minnesota, Michael moved back to the applied to rod-shaped plant viruses Michael Rossmann made seminal UK to join Max Perutz, John Kendrew and icosahedrally symmetric viruses Icontributions to the field of protein and Dorothy Hodgkin in the Medical such as rhinovirus (the ‘common cold’ structure. Although possibly best known Research Council’s ‘hut’ adjacent to the virus). This structure, published in 1985, to microbiologists for his structures of Cavendish Laboratory in Cambridge. provided important insights into the icosahedral viruses, he was also the Michael worked with Perutz and biology of the virus. These included the first to define conserved nucleotide- Kendrew to solve the structure of canyon hypothesis, which described a binding motifs in proteins (the Rossmann haemoglobin, the first protein to have conserved receptor-binding cleft, hidden fold) and developed the molecular its structure reported. Following this, from the host immune system, and replacement method used to solve with David Blow, Michael developed the presence of a particle-stabilising around 75% of structures submitted novel phasing methods for solving sphingosine, displaced upon receptor annually to the Protein Data Bank (PDB). protein structures. These methods, binding. The principles of a metastable Michael was born in Frankfurt, now known as molecular replacement, virus particle with an antibody-protected Germany, and educated in the UK from are fundamental to the solution of receptor-interacting domain are now well 1939. His undergraduate degrees were thousands of structures today. established in virology. in Mathematics and Physics from the In 1964, Michael moved to an The principle of structure informing University of London and his doctorate, Associate Professor position in Biological function was continued in studies of in chemical crystallography, was from Sciences at Purdue University, Indiana. enveloped viruses such as dengue and the University of Glasgow in 1956. After In 1978 he was appointed the Hanley Zika, the packaging motors of phages two years as a postdoc at the University Distinguished Professor of Biological that form exquisite molecular machines Sciences at Purdue University, a position and the giant Mimiviruses. he held for the rest of his long career. These achievements reflected the While at Cambridge, Michael learnt energy and enthusiasm Michael brought that the mathematical puzzles of to solving the structures of life and were crystallography, although challenging recognised in accolades from around in their own right, provided the key to the world. Michael was a member of the understanding nature, in particular the National Academy of Sciences (USA), a relationship between the structure and Foreign Member of the Royal Society (UK), function of proteins. a recipient of the Gregori Aminoff Prize At Purdue University, Michael (awarded by the Royal Swedish Academy conducted comparative structural of Sciences) and a presidential appointee analysis of divergent dehydrogenases to the National Science Board (USA). and identified a fundamentally conserved protein fold that bound David J. Evans nicotinamide adenine dinucleotide [email protected] (NAD). This Rossmann fold is the most

Microbiology Today Nov 19 | microbiologysociety.org 193 Reviews

Infection Prevention and Control: Typically, publications on IPC focus primarily on the Perceptions and Perspectives scientific and technical aspects of infection control. Infection Prevention and Control: Perceptions and Perspectives, however, Edited by Paul Elliott, Julie Storr and Annette Jeanes introduces a novel way of thinking. The book is wide-ranging CRC Press (2015) £38.99 ISBN 978-184619-989-9 and includes the perspectives of not only those providing the It is no secret that now even the shortest of care but also of the patient and family, giving a voice to those hospital stays drastically increases your risk who receive healthcare and highlighting the key role they of developing a hospital-acquired/healthcare-associated also play in infection prevention. It also stresses leadership infection (HAI). HAIs are associated with extended hospital throughout, emphasising that without effective direction and stays, high care costs and an increased risk of death for management at all levels, there can be no further both patients and healthcare facilities worldwide. Infection improvements. prevention and control (IPC) is an essential element of patient Whilst this book is less likely to be suitable for someone safety and is the responsibility of all those who provide care. lacking a sound background knowledge of IPC, it provides Whilst not all HAIs are preventable, in many cases they a new and stimulating perspective and would be highly are no longer considered an acceptable adverse event during beneficial for those looking to further their professional a hospital stay, especially in the face of ever-increasing development. antimicrobial resistance. Extensive IPC policies are in place, such as hand hygiene and global antibiotic stewardship. Helina Marshall However, as antibiotic resistance begins to surpass novel Queen’s University Belfast, UK discovery and development, it is clear that perhaps novel For more reviews, please visit the online issue of Microbiology approaches are required, before many aspects of modern Today at microbiologysociety.org/microbiologytoday. medicine are no longer viable.

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down the path of personalised medicine, this will continue to challenge the bio- Industry pharmaceutical industry. Indeed, one of the biggest challenges we face, antibiotic resistance, is impacted by this scenario. Any new antibiotic will, by definition, be insights in drug highly restricted on use to inhibit further resistance mechanisms. In prescribing this business model, the pressures on the associated manufacturing costs development would be significant and could slow progression to market. Michael Bagnall Commercial supply Delivering life-changing medicines within today’s bio-pharmaceutical industry In order to combat manufacturing costs, Contract Manufacturing is a complex operation informed by early development decisions, and the time, Organisations (CMOs) are often investment and tenacity of our teams is not always visible to our most important used. These CMOs offer a platform stakeholder, our patient. The following short narrative will highlight some of the of manufacturing operations from high-potency powder handling, sterile challenges we face as we transform the lives of millions of patients every day. containment for primary container closure, through to full co-packed Discovery cost can be offset against the longevity combination product. Here the issue When considering molecules for drug of the commercial lifecycle, essentially is now one of capacity. Given the candidacy in Phase I trials, a bench recouping the costs over a number of financial constraints highlighted, there scientist may not have formed an years when the treatment is protected are ever-increasing demands for CMO optimised manufacturing process. by a patent. Increasingly, however, the manufacture; these by nature are However, as we are recognising at Merck molecules identified are for small patient specialised and, as such, a very small Sharp & Dohme (MSD), we need to embed populations and, as we progress further pool of manufacturing companies exists. manufacturing considerations earlier on in the development pathway for critical success. We realise that manufacturing technologies are a key corner stone for the successful production of molecules and, as we progress to more bespoke molecules, a number of critical elements need to be addressed as early in the process as possible.

Assume you have discovered a new antibiotic – what next? Manufacturing costs are often multiple millions of pounds if a bespoke facility is required. Should the molecule in question be for a large-scale public health issue (for example, cholesterol, diabetes) this Sterile bottles on the bottling line of a pharmaceutical plant. Neznam/iStock

Microbiology Today Nov 19 | microbiologysociety.org 195 Consider your antibiotic; this has been Key constraint considerations complex final product import testing to refined to a sterile powder formulated What is the demonstrated product be conducted, rendering the shipment into sterile cartridges for an auto injector. stability? What manufacturing useless as the product is now There is a minimal list of potential requirements do we have? Explosive ineffective. Both scenarios restrict suppliers, assuming a platform existed. risks associated with powders? Cold product availability for our patients. Once secured, the manufacturing plan chain storage? Light protection? Sterile Supply chains are the mechanism will need to be negotiated. Typically, these barrier breakdown? Analytical release for getting our medicines to our types of platforms offer total capacity of methods? Import analytical methods? patients. I have offered an insight into hundreds of millions of units per year. Provision of inputs? A casual look at this this increasingly complex and globally If we look to supply a Phase III clinical list may seem overwhelming, a missed dispersed operation in order to highlight study, we could need a fraction of this step here would be a costly mistake. the challenges faced and how these, if (2,000–5,000 units) and for a restricted- Consider influenza vaccine considered early, can be overcome. use antibiotic the commercial volumes production – global production of egg- Despite the challenges, we must will continue to be low, meaning we are based flu vaccine is constrained by the continue to innovate for our patients and just a small part of the CMOs’ ‘book of number of eggs available. Consider a deliver life-changing medicines from the business’. temperature-sensitive oncology therapy drug discovery lab bench through to the held incorrectly at an airport to allow end of the supply chain. Regulatory landscape The regulatory landscape has Michael Bagnall never before been so dynamic and Virtual Plant Manager – External Manufacturing Operations, demanding. With the onset of the US Manufacturing Division, Merck Sharp & Dohme Limited, Food and Drug Administration (FDA) Registered Office Hertford Road, Hoddesdon, Hertfordshire Medical Device and Combination EN11 9BU, UK Products legislation and the European e [email protected]

Union Medical Device Directive (MDD), Michael Bagnall Living with his wife and daughter in the Peak District, Mike the path for any new delivery system and graduated from University of Wales (Aberystwyth, UK) in active pharmaceutical ingredient (API) is 2004 with a BSc in Microbiology. Mike has 15 years’ pharmaceutical operations much more complex. A device (bespoke experience, from drug development to full-scale commercial production/plant or platform) will require a design management. Now working within MSDs External Manufacturing Team, Mike history file or technical manual if a CE manages the external production at various vendor factories globally. mark is mandated. These regulations increased following the Poly Implant On a typical day (or week) in your position what do you do? Prothèse (PIP) breast implant recall in A typical day as a Virtual Plant Manager is anything but typical! A day might 2010, including human factor testing, start with releasing production orders for my CMO to produce, ratifying and user harms assessments and toxicology approving the five-year production plan. There may be a team meeting with my requirements to name a few. Combined focus factory to understand the quality, technical and operations tasks needed with the traditional New Drug Application in the short term. Other tasks may include switching to a production schedule (NDA) requirements, these are built review with the CMO, Brexit planning, trade dispute oversight (for supply chain into MSD’s drug/device development disruption), invoice approvals, strategic project review meetings, to name a few. to ensure our products are safe and It’s certainly never, ever dull. effective. When a fully-approved product is What inspired you to become a microbiologist? ready for market, the constraints built When you consider that a small bundle of fairly simple proteins, lumped together, in at the beginning of drug discovery can either kill you or produce an antibiotic that saves billions, it’s easy to be then play a critical role in the agility and inspired! I wanted to understand this world in all of its wonderful complexity. responsiveness of supply.

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