Chem Soc Rev View Article Online REVIEW ARTICLE View Journal | View Issue The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and Cite this: Chem. Soc. Rev., 2021, 50, 7820 future directions Bee Ha Gan, † Josephine Gaynord, † Sam M. Rowe, † Tomas Deingruber † and David R. Spring * Bacterial infections caused by ‘superbugs’ are increasing globally, and conventional antibiotics are becoming less effective against these bacteria, such that we risk entering a post-antibiotic era. In recent years, antimicrobial peptides (AMPs) have gained significant attention for their clinical potential as a new class of antibiotics to combat antimicrobial resistance. In this review, we discuss several facets of AMPs including their diversity, physicochemical properties, mechanisms of action, and effects of environmental factors on these features. This review outlines various chemical synthetic strategies that Received 30th November 2020 have been applied to develop novel AMPs, including chemical modifications of existing peptides, semi- Creative Commons Attribution 3.0 Unported Licence. DOI: 10.1039/d0cs00729c synthesis, and computer-aided design. We will also highlight novel AMP structures, including hybrids, antimicrobial dendrimers and polypeptides, peptidomimetics, and AMP–drug conjugates and consider rsc.li/chem-soc-rev recent developments in their chemical synthesis. 1 A brief history of antibiotics and the however it has become somewhat synonymous with antibacterial agents.1 Today the term antimicrobial is often used in place of current state of play antibiotic to emphasise the inclusion of antiviral, antifungal This article is licensed under a Antibiotics are chemicals which either kill or prevent the and antiparasitic agents, although both terms can be used growth of microbes. The word ‘antibiotic’ means ‘anti-life’, interchangeably and will be used as such throughout. When appropriate, the specific terms, e.g. antibacterial, antifungal, will be used. Most of the antimicrobial research has focussed Open Access Article. Published on 27 May 2021. Downloaded 10/9/2021 11:17:26 AM. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. E-mail: [email protected] on antibacterial agents and therefore much of the discussion † Authors have contributed equally to this work. presented here will focus on this subclass. However, we direct Bee Ha Gan received her MSc in Josephine Gaynord obtained her Molecular Biology at the Bio- MSci in chemistry from the Uni- zentrum of the University of versity of Nottingham in 2016. Basel (Switzerland) in 2014. She During this time, she spent a obtained her PhD in Chemical year at Takeda Cambridge as a Biology at the University of Bern medicinal chemistry placement (Switzerland) in 2019, where her student and completed a colla- research focused on antimicrobial borative GlaxoSmithKline medi- peptides and peptide dendrimers cinal chemistry masters project under the supervision of Prof. working on novel integrin inhi- Jean-Louis Reymond. Bee Ha is bitors. In 2016 she started her currently a postdoctoral researcher PhD under the supervision of Bee Ha Gan in the group of Prof. David Spring Josephine Gaynord Professor David Spring at the at the University of Cambridge and University of Cambridge, resear- her research focuses on developing novel peptide–drug conjugates for ching the use of stapled peptides to inhibit protein–protein inter- antimicrobial applications. actions in human platelets and as antimicrobial peptide–drug conjugates. 7820 | Chem. Soc. Rev., 2021, 50, 7820–7880 This journal is © The Royal Society of Chemistry 2021 View Article Online Review Article Chem Soc Rev Table 1 An overview of the major classes of antibiotics, with key examples, targets, and sources. Adapted from Brown and Wright11 Class Example Target Source Sulfonamides Sulfanilamide Folate synthesis Synthetic Fluoroquinolones Ciprofloxacin DNA topoisomerases Synthetic b-Lactams Ceftazidime Cell wall synthesis Natural product Oxazolidinones Linezolid Protein synthesis Synthetic Aminoglycosides Neomycin Protein synthesis Natural product Glycopeptides Vancomycin Cell wall synthesis Natural product Polymyxins Polymyxin B Bacterial cell membrane Natural product Cyclic lipopeptides Daptomycin Bacterial cell membrane Natural product Tetracyclines Tetracycline Protein synthesis Natural product the reader to Section 16 for a dedicated discussion of other synthetic antimicrobial agent.3 Marketed as ‘Salvarsan’ in 1910, subclasses. arsphenamine was the first effective treatment for syphilis, Humankind has employed antimicrobials for millennia with which had been one of the largest public health burdens documented examples of herbs, honey, and mouldy bread being in the 16th through 19th centuries. Sir Alexander Fleming’s used in ancient Egypt, China, and Rome to treat infections.2 serendipitous discovery of penicillin G in 1928 was the next While developing dyes for bacterial stains in the early 20th significant milestone in the history of drug discovery. The century, Paul Ehrlich observed that some compounds displayed translation of Fleming’s research into an extremely effective, an antibacterial effect. This inspired the search for a ‘magic mass-produced medicine saved thousands of lives, leading bullet’ – a drug which would selectively kill disease-causing to penicillin being known as ‘the wonder drug’. This break- organisms while sparing the human patient. This search through triggered a race to develop similarly effective antimi- culminated in the discovery of arsphenamine in 1909: the first crobials and has ultimately led to the drug discovery landscape Creative Commons Attribution 3.0 Unported Licence. we see today.4 In 2019, the WHO published the 21st Essential Medicines List which includes over 40 antimicrobials.5 These drugs can be sourced directly from nature; synthesised from Sam Rowe received his PhD from simple building blocks in a laboratory; or a combination of the the University of Cambridge two whereby a complex molecule is sourced from nature and (2021) under the supervision of then further synthetically modified (semi-synthesis). Some of Professor David R. Spring. His the major classes of antibiotics, which have been reviewed PhD work involved developing extensively elsewhere, are listed in Table 1.1,2,7 peptide and stapled peptide Despite increasingly sophisticated approaches to antimicro- This article is licensed under a tools to investigate therapeuti- bial discovery and development, these drugs have several cally-relevant biological targets. common limitations. Among the most restrictive is poor bio- He currently works at GSK as a availability, which necessitates regular and high dosing in Open Access Article. Published on 27 May 2021. Downloaded 10/9/2021 11:17:26 AM. peptide synthesis expert within order to maintain a sufficient concentration of drug at the site the chemical biology team. of infection.6 Another major issue is systemic toxicity, which is inherent for some classes of antibiotics. For example, Sam M. Rowe nephro- and neuro-toxicity limit the clinical use of polymyxins, Tomas Deingruber received his David Spring is currently Prof- MSci from the University of essor of Chemistry and Chemical Cambridge in 2019, having Biology at the University of completed his masters project on Cambridge within the Chemistry synthesis of multi-functional Department. He received his unnatural amino acids in the DPhil (1998) at Oxford Univer- group of Professor Jason Chin at sity under Sir Jack Baldwin. He MRC Laboratory of Molecular then worked as a Wellcome Trust Biology. In the same year he Postdoctoral Fellow at Harvard started his PhD studies under University with Stuart Schreiber the supervision of Professor (1999–2001), after which he David Spring at the University of joined the faculty at the Univer- Tomas Deingruber Cambridge. His current research David R. Spring sity of Cambridge. His research focuses on synthesis of peptide– programme is focused on the use drug conjugates. of chemistry to explore biology. This journal is © The Royal Society of Chemistry 2021 Chem. Soc. Rev., 2021, 50, 7820–7880 | 7821 View Article Online Chem Soc Rev Review Article the last-resort drugs for Pseudomonas aeruginosa infections.7 The second category, known as ‘opportunistic pathogens’, are The US Food and Drug Administration (FDA) have also recently environmental bacteria that only display pathogenicity in an updated their guidance for the use of fluoroquinolone anti- immunocompromised host. Pseudomonas aeruginosa, Stenotro- biotics due to the possibility of life-threatening side effects in phomonas maltophilia, Acinetobacter baumannii,andBurkholderia patients with low blood sugar.8 Broad-spectrum antibiotics, cepacia belong to this class.18 In 2017, the WHO identified which are able to kill multiple species of microorganism, enable Pseudomonas spp., Acinetobacter spp., and Enterobacteriaceae as the rapid treatment of undiagnosed infections. However, over- the three groups of pathogens with the most critical need for reliance on these ‘catch-all’ therapeutics has become increasingly new antibiotics. These pathogens were identified as displaying recognised as a significant contributor to the growing antimicro- widespread MDR and posing a threat to hospitals, nursing bial resistance (AMR) crisis. Furthermore, since the targets of homes, and to patients who require devices such as ventilators these antibiotics are conserved among multiple species, they risk and catheters.