Antimicrobial Lipopeptide Tridecaptin A1 Selectively Binds to Gram-Negative Lipid II
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
A New Antibiotic Kills Pathogens Without Detectable Resistance
ARTICLE doi:10.1038/nature14098 A new antibiotic kills pathogens without detectable resistance Losee L. Ling1*, Tanja Schneider2,3*, Aaron J. Peoples1, Amy L. Spoering1, Ina Engels2,3, Brian P. Conlon4, Anna Mueller2,3, Till F. Scha¨berle3,5, Dallas E. Hughes1, Slava Epstein6, Michael Jones7, Linos Lazarides7, Victoria A. Steadman7, Douglas R. Cohen1, Cintia R. Felix1, K. Ashley Fetterman1, William P. Millett1, Anthony G. Nitti1, Ashley M. Zullo1, Chao Chen4 & Kim Lewis4 Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance. Widespread introduction of antibiotics in the 1940s, beginning with factors through the chambers enables growth of uncultured bacteria in penicillin1,2 and streptomycin3, transformed medicine, providing effec- their natural environment. -
Novel Antimicrobial Agents Inhibiting Lipid II Incorporation Into Peptidoglycan Essay MBB
27 -7-2019 Novel antimicrobial agents inhibiting lipid II incorporation into peptidoglycan Essay MBB Mark Nijland S3265978 Supervisor: Prof. Dr. Dirk-Jan Scheffers Molecular Microbiology University of Groningen Content Abstract..............................................................................................................................................2 1.0 Peptidoglycan biosynthesis of bacteria ........................................................................................3 2.0 Novel antimicrobial agents ...........................................................................................................4 2.1 Teixobactin ...............................................................................................................................4 2.2 tridecaptin A1............................................................................................................................7 2.3 Malacidins ................................................................................................................................8 2.4 Humimycins ..............................................................................................................................9 2.5 LysM ........................................................................................................................................ 10 3.0 Concluding remarks .................................................................................................................... 11 4.0 references ................................................................................................................................. -
Brilacidin First-In-Class Defensin-Mimetic Drug Candidate
Brilacidin First-in-Class Defensin-Mimetic Drug Candidate Mechanism of Action, Pre/Clinical Data and Academic Literature Supporting the Development of Brilacidin as a Potential Novel Coronavirus (COVID-19) Treatment April 20, 2020 Page # I. Brilacidin: Background Information 2 II. Brilacidin: Two Primary Mechanisms of Action 3 Membrane Disruption 4 Immunomodulatory 7 III. Brilacidin: Several Complementary Ways of Targeting COVID-19 10 Antiviral (anti-SARS-CoV-2 activity) 11 Immuno/Anti-Inflammatory 13 Antimicrobial 16 IV. Brilacidin: COVID-19 Clinical Development Pathways 18 Drug 18 Vaccine 20 Next Steps 24 V. Brilacidin: Phase 2 Clinical Trial Data in Other Indications 25 VI. AMPs/Defensins (Mimetics): Antiviral Properties 30 VII. AMPs/Defensins (Mimetics): Anti-Coronavirus Potential 33 VIII. The Broader Context: Characteristics of the COVID-19 Pandemic 36 Innovation Pharmaceuticals 301 Edgewater Place, Ste 100 Wakefield, MA 01880 978.921.4125 [email protected] Innovation Pharmaceuticals: Mechanism of Action, Pre/Clinical Data and Academic Literature Supporting the Development of Brilacidin as a Potential Novel Coronavirus (COVID-19) Treatment (April 20, 2020) Page 1 of 45 I. Brilacidin: Background Information Brilacidin (PMX-30063) is Innovation Pharmaceutical’s lead Host Defense Protein (HDP)/Defensin-Mimetic drug candidate targeting SARS-CoV-2, the virus responsible for COVID-19. Laboratory testing conducted at a U.S.-based Regional Biocontainment Laboratory (RBL) supports Brilacidin’s antiviral activity in directly inhibiting SARS-CoV-2 in cell-based assays. Additional pre-clinical and clinical data support Brilacidin’s therapeutic potential to inhibit the production of IL-6, IL-1, TNF- and other pro-inflammatory cytokines and chemokines (e.g., MCP-1), identified as central drivers in the worsening prognoses of COVID-19 patients. -
Current Topics in Medicinal Chemistry, 2017, 17, 576-589
576 Send Orders for Reprints to [email protected] Current Topics in Medicinal Chemistry, 2017, 17, 576-589 REVIEW ARTICLE ISSN: 1568-0266 eISSN: 1873-5294 Impact Factor: Mimics of Host Defense Proteins; Strategies for Translation to Therapeutic 2.9 The international journal for in-depth reviews on Applications Current Topics in Medicinal Chemistry BENTHAM SCIENCE Richard W. Scott*,1 and Gregory N. Tew2 1Fox Chase Chemical Diversity Center, Pennsylvania Biotechnology Center, Doylestown, PA, USA; 2Polymer Science and Engineering, Veterinary and Animal Science, Cell and Molecular Biology, University of Massachusetts, Amherst MA, USA Abstract: New infection treatments are urgently needed to combat the rising threat of multi-drug re- sistant bacteria. Despite early clinical set-backs attention has re-focused on host defense proteins (HDPs), as potential sources for new and effective antimicrobial treatments. HDPs appear to act at multiple targets and their repertoire includes disruptive membrane and intracellular activities against numerous types of pathogens as well as immune modulatory functions in the host. Importantly, these novel activities are associated with a low potential for emergence of resistance and little cross- resistance with other antimicrobial agents. Based on these properties, HDPs appear to be ideal candi- A R T I C L E H I S T O R Y dates for new antibiotics; however, their development has been plagued by the many therapeutic limi- tations associated with natural peptidic agents. This review focuses on HDP mimetic approaches Received: May 22, 2015 Revised: October 29, 2015 aimed to improve metabolic stability, pharmacokinetics, safety and manufacturing processes. Early ef- Accepted: November 30, 2015 forts with β-peptide or peptoid analogs focused on recreating stable facially amphiphilic structures but DOI: 10.2174/15680266166661607 demonstrated that antimicrobial activity was modulated by more, complex structural properties. -
Antibiotic Use Guidelines for Companion Animal Practice (2Nd Edition) Iii
ii Antibiotic Use Guidelines for Companion Animal Practice (2nd edition) iii Antibiotic Use Guidelines for Companion Animal Practice, 2nd edition Publisher: Companion Animal Group, Danish Veterinary Association, Peter Bangs Vej 30, 2000 Frederiksberg Authors of the guidelines: Lisbeth Rem Jessen (University of Copenhagen) Peter Damborg (University of Copenhagen) Anette Spohr (Evidensia Faxe Animal Hospital) Sandra Goericke-Pesch (University of Veterinary Medicine, Hannover) Rebecca Langhorn (University of Copenhagen) Geoffrey Houser (University of Copenhagen) Jakob Willesen (University of Copenhagen) Mette Schjærff (University of Copenhagen) Thomas Eriksen (University of Copenhagen) Tina Møller Sørensen (University of Copenhagen) Vibeke Frøkjær Jensen (DTU-VET) Flemming Obling (Greve) Luca Guardabassi (University of Copenhagen) Reproduction of extracts from these guidelines is only permitted in accordance with the agreement between the Ministry of Education and Copy-Dan. Danish copyright law restricts all other use without written permission of the publisher. Exception is granted for short excerpts for review purposes. iv Foreword The first edition of the Antibiotic Use Guidelines for Companion Animal Practice was published in autumn of 2012. The aim of the guidelines was to prevent increased antibiotic resistance. A questionnaire circulated to Danish veterinarians in 2015 (Jessen et al., DVT 10, 2016) indicated that the guidelines were well received, and particularly that active users had followed the recommendations. Despite a positive reception and the results of this survey, the actual quantity of antibiotics used is probably a better indicator of the effect of the first guidelines. Chapter two of these updated guidelines therefore details the pattern of developments in antibiotic use, as reported in DANMAP 2016 (www.danmap.org). -
Swedres-Svarm 2010
SVARM|2010 Swedish Veterinary Antimicrobial Resistance Monitoring Content Swedish Veterinary Antimicrobial Resistance Monitoring 2010 Preface .............................................................................................3 Guidance for readers ........................................................................4 Editors Summary ..........................................................................................5 Björn Bengtsson, Helle Ericsson Unnerstad, Sammanfattning...............................................................................7 Christina Greko, Ulrika Grönlund Andersson and Annica Landén Use of antimicrobials .......................................................................9 Department of Animal Health and Zoonotic bacteria ...........................................................................14 Antimicrobial Strategies, National Veterinary Salmonella ...................................................................................14 Institute (SVA) SE-751 89 Uppsala, Sweden Campylobacter .............................................................................18 Methicillin resistant Staphylococcus aureus (MRSA) ....................19 Authors Highlight: Escherichia coli with ESBL - or transferrable Björn Bengtsson, Helle Ericsson Unnerstad, AmpC-type resistance in broilers .............................................22 Christina Greko, Ulrika Grönlund Andersson and Annica Landén Indicator bacteria ...........................................................................24 -
Conjunctivitis Or Worse?
Red Eye in Dogs and CatS: Conjunctivitis or Worse? Tracy Revoir, DVM Senior Manager of Veterinary Support, Dechra Veterinary Products It should come as no surprise that conjunctivitis is Common Causes of Conjunctivitis the most common ophthalmic disorder in dogs and cats. But because the clinical signs of conjunctivitis If you do confirm conjunctivitis, the next step is can mimic those of more serious ophthalmic identifying the cause. If both eyes are affected and diseases (glaucoma and uveitis), it’s important to abnormal clinical signs are apparent in other body confirm your diagnosis. systems, think underlying systemic disease. If only one eye is affected, rule out infection, tear film What are important clues to the severity of the deficiencies, an irritant, anatomical abnormality, condition? With conjunctivitis, the inflammation or deeper ocular disease. should be limited to the conjunctiva. Hyperemic conjunctival vessels are superficial, branching, In dogs, conjunctivitis can result from anatomical and bright red. They are movable over the deeper disorders, irritants, infection (usually bacterial), or episcleral vessels and can be blanched with topical atopy. Most bacterial infections are secondary dilute phenylephrine. With glaucoma and uveitis, the conditions, most often to allergies. In cats, herpes- episcleral vessels are engorged; they are dark red, virus and Chlamydophila felis are the most common deep, straight, and immobile and do not blanch with causes of conjunctivitis. Atopy can also be topical dilute phenylephrine. With conjunctivitis, an issue in cats. the Schirmer tear test and intraocular pressures are normal. And the cornea should be clear and no aqueous flare should be present. The pupil and Addressing the Problem pupillary responses are normal and intraocular structures should be visible. -
Escherichia Coli K–12 Derived from the Ecocyc Database Daniel S Weaver1*,Ingridmkeseler1,Amandamackie2, Ian T Paulsen2 and Peter D Karp1
Weaver et al. BMC Systems Biology 2014, 8:79 http://www.biomedcentral.com/1752-0509/8/79 RESEARCH ARTICLE OpenAccess A genome-scale metabolic flux model of Escherichia coli K–12 derived from the EcoCyc database Daniel S Weaver1*,IngridMKeseler1,AmandaMackie2, Ian T Paulsen2 and Peter D Karp1 Abstract Background: Constraint-based models of Escherichia coli metabolic flux have played a key role in computational studies of cellular metabolism at the genome scale. We sought to develop a next-generation constraint-based E. coli model that achieved improved phenotypic prediction accuracy while being frequently updated and easy to use. We also sought to compare model predictions with experimental data to highlight open questions in E. coli biology. Results: We present EcoCyc–18.0–GEM, a genome-scale model of the E. coli K–12 MG1655 metabolic network. The model is automatically generated from the current state of EcoCyc using the MetaFlux software, enabling the release of multiple model updates per year. EcoCyc–18.0–GEM encompasses 1445 genes, 2286 unique metabolic reactions, and 1453 unique metabolites. We demonstrate a three-part validation of the model that breaks new ground in breadth and accuracy: (i) Comparison of simulated growth in aerobic and anaerobic glucose culture with experimental results from chemostat culture and simulation results from the E. coli modeling literature. (ii) Essentiality prediction for the 1445 genes represented in the model, in which EcoCyc–18.0–GEM achieves an improved accuracy of 95.2% in predicting the growth phenotype of experimental gene knockouts. (iii) Nutrient utilization predictions under 431 different media conditions, for which the model achieves an overall accuracy of 80.7%. -
Polymyxin B & Colistin Dosing Tip Sheet
Stanford Antimicrobial Safety & Sustainability Program Polymyxin B & Colistin Dosing Tip Sheet What: Polymyxin B is preferred over Colistin (polymyxin E) for infections due to multidrug resistant gram- negative bacilli at Stanford Health Care. SHC formulary restriction criteria – Polymyxin B 1. Infectious Disease Consultation and ID recommendation for use 2. Cystic Fibrosis team SHC formulary restriction criteria – Colistin 1. Treatment of urinary tract infections 2. Inhalation route Why: Polymyxin B and Colistin have the same spectrum of activity. However, Polymyxin B has favorable clinical pharmacologic properties compared to Colistin o Polymyxin B is an active drug, whereas Colistin is administered as the prodrug colistimethate sodium (CMS) and has variable and slow (hours) conversion to the active moiety o Polymyxin B may be less nephrotoxic How: Polymyxin B and Colistin dosing is NOT interchangeable o Polymyxin B is usually dosed by “unit”, not “mg” o Note that with Polymyxin B, each 500,000 units is diluted in 300-500mL: a typical dose may result in 1L of fluid o Consult ID pharmacists if MIC ≥ 2 for alternative dosing strategies Dosing 50-79 30-49 10-29 IHD Route ≥80 mL/min mL/min mL/min mL/min CRRT Polymyxin B No Data; Use actual body IV 7,500 – 12,500 units/kg Q12H Consult ID weight; adjusted body wt for obese pharmacist 2.5 mg/kg 1.5 mg/kg 5 mg/kg/day 1.25–1.9 mg/kg Q24H 1.5 mg/kg Q24-48h Colistin IV in 2-3 divided -OR- Use ideal body Q12H Q36H 2.5 mg/kg weight doses 1.25 mg/kg Q12h Q12-24H Doses expressed in colistin base activity Inhalation 150 mg inhalation Q12H Conversions: Colistimethate sodium 1 mg = ~12,500 units of colistimethate sodium Colistimethate sodium ~2.67 mg = 1 mg of colistin base activity 1 mg colistin base activity (CBA) = 30,000 IU colistin 1 mg polymyxin B = 10,000 IU polymyxin B Orig date: 2/23/2015 LM, EM Stanford Antimicrobial Safety & Sustainability Program References: Micromedex online, accessed 2/17/2016 Nelson, Brian C., et al. -
Farrukh Javaid Malik
I Farrukh Javaid Malik THESIS PRESENTED TO OBTAIN THE GRADE OF DOCTOR OF THE UNIVERSITY OF BORDEAUX Doctoral School, SP2: Society, Politic, Public Health Specialization Pharmacoepidemiology and Pharmacovigilance By Farrukh Javaid Malik “Analysis of the medicines panorama in Pakistan – The case of antimicrobials: market offer width and consumption.” Under the direction of Prof. Dr. Albert FIGUERAS Defense Date: 28th November 2019 Members of Jury M. Francesco SALVO, Maître de conférences des universités – praticien hospitalier, President Université de Bordeaux M. Albert FIGUERAS, Professeur des universités – praticien hospitalier, Director Université Autonome de Barcelone Mme Antonia AGUSTI, Professeure, Vall dʹHebron University Hospital Referee Mme Montserrat BOSCH, Praticienne hospitalière, Vall dʹHebron University Hospital Referee II Abstract A country’s medicines market is an indicator of its healthcare system, the epidemiological profile, and the prevalent practices therein. It is not only the first logical step to study the characteristics of medicines authorized for marketing, but also a requisite to set up a pharmacovigilance system, thus promoting rational drug utilization. The three medicines market studies presented in the present document were conducted in Pakistan with the aim of describing the characteristics of the pharmaceutical products available in the country as well as their consumption at a national level, with a special focus on antimicrobials. The most important cause of antimicrobial resistance is the inappropriate consumption of antimicrobials. The results of the researches conducted in Pakistan showed some market deficiencies which could be addressed as part of the national antimicrobial stewardship programmes. III Résumé Le marché du médicament d’un pays est un indicateur de son système de santé, de son profil épidémiologique et des pratiques [de prescription] qui y règnent. -
Belgian Veterinary Surveillance of Antibacterial Consumption National
Belgian Veterinary Surveillance of Antibacterial Consumption National consumption report 2020 Publication : 22 June 2021 1 SUMMARY This annual BelVet-SAC report is now published for the 12th time and describes the antimicrobial use (AMU) in animals in Belgium in 2020 and the evolution since 2011. For the third year this report combines sales data (collected at the level of the wholesalers-distributors and the compound feed producers) and usage data (collected at farm level). This allows to dig deeper into AMU at species and farm level in Belgium. With a consumption of 87,6 mg antibacterial compounds/kg biomass an increase of +0.2% is seen in 2020 in comparison to 2019. The increase seen in 2020 is spread over both pharmaceuticals (+0.2%) and antibacterial premixes (+4.0%). This unfortunately marks the end of a successful reduction in antibacterial product sales that was seen over the last 6 years resulting in a cumulative reduction of -40,2% since 2011. The gap seen in the coverage of the sales data with the Sanitel-Med collected usage data increased substantially compared to 2019, meaning continuous efforts need to be taken to ensure completeness of the collected usage data. When looking at the evolution in the number of treatment days (BD100) at the species level, as calculated from the SANITEL- MED use data, use increased in poultry (+5,0%) and veal calves (+1,9%), while it decreased in pigs (-3,1%). However, the numerator data for this indicator remain to be updated for 2020, potentially influencing the reliability of the result. -
Synthesis and Structure−Activity Relationships of Teixobactin
Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Special Issue: Antimicrobial Therapeutics Reviews REVIEW Synthesis and structure−activity relationships of teixobactin John A. Karas,1 Fan Chen,1 Elena K. Schneider-Futschik,1,2 Zhisen Kang,1 Maytham Hussein,1 James Swarbrick,1 Daniel Hoyer,1,3,4 Andrew M. Giltrap,5 Richard J. Payne,5 Jian Li,6 and Tony Velkov1 1Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, the University of Melbourne, Parkville, Victoria, Australia. 2Lung Health Research Centre, Department of Pharmacology & Therapeutics, the University of Melbourne, Parkville, Victoria, Australia. 3The Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville, Victoria, Australia. 4Department of Molecular Medicine, the Scripps Research Institute, La Jolla, California. 5School of Chemistry, the University of Sydney, Sydney, New South Wales, Australia. 6Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia Address for correspondence: Tony Velkov and John A. Karas, Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, the University of Melbourne, Parkville, VIC 3010, Australia. [email protected] OR [email protected] The discovery of antibiotics has led to the effective treatment of bacterial infections that were otherwise fatal and has had a transformative effect on modern medicine. Teixobactin is an unusual depsipeptide natural product that was recently discovered from a previously unculturable soil bacterium and found to possess potent antibacterial activity against several Gram positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin- resistant Enterococci.