Antimicrobial peptides (AMPs) have been studied for three decades, and yet a molecular understanding of their mechanism of action is still lacking. Here we summarize current knowledge for both synthetic vesicle experiments and microbe experiments, with a focus on comparisons between the two. Microbial experiments are done at peptide to lipid ratios that are at least 4 orders of magnitude higher than vesicle-based experiments. To close the gap between the two concentration regimes, we propose an “interfacial activity model”, which is based on an experimentally testable molecular image of AMP–membrane interactions. The interfacial activity model may be useful in driving engineering and design of novel AMPs.

/pdf/describing-the-mechanism-of-antimicrobial-peptide-action-s12jfh4a9i.pdf

Describing the mechanism of antimicrobial peptide action with the interfacial activity model.

Antimicrobial peptides (AMPs) are promising next generation antibiotics that hold great potential for combating bacterial resistance. AMPs can be both bacteriostatic and bactericidal, induce rapid killing and display a lower propensity to develop resistance than do conventional antibiotics. Despite significant progress in the past 30 years, no peptide antibiotic has reached the clinic yet. Poor understanding of the action mechanisms and lack of rational design principles have been the two major obstacles that have slowed progress. Technological developments are now enabling multidisciplinary approaches including molecular dynamics simulations combined with biophysics and microbiology toward providing valuable insights into the interactions of AMPs with membranes at atomic level. This has led to increasingly robust models of the mechanisms of action of AMPs and has begun to contribute meaningfully toward the discovery of new AMPs. This review discusses the detailed action mechanisms that have been put forward, with detailed atomistic insights into how the AMPs interact with bacterial membranes. The review further discusses how this knowledge is exploited towards developing design principles for novel AMPs. Finally, the current status, associated challenges and future directions for the development of AMP therapeutics are discussed.

/pdf/membrane-active-antimicrobial-peptides-translating-1s23pm69zp.pdf

Membrane Active Antimicrobial Peptides: Translating Mechanistic Insights to Design.

Naturally occurring cationic antimicrobial peptides (AMPs) and their mimics form a diverse class of antibacterial agents currently validated in preclinical and clinical settings for the treatment of infections caused by antimicrobial-resistant bacteria Numerous studies with linear, cyclic, and diastereomeric AMPs have strongly supported the hypothesis that their physicochemical properties, rather than any specific amino acid sequence, are responsible for their microbiological activities It is generally believed that the amphiphilic topology is essential for insertion into and disruption of the cytoplasmic membrane In particular, the ability to rapidly kill bacteria and the relative difficulty with which bacteria develop resistance make AMPs and their mimics attractive targets for drug development However, the therapeutic use of naturally occurring AMPs is hampered by the high manufacturing costs, poor pharmacokinetic properties, and low bacteriological efficacy in animal models In order to overcome these problems, a variety of novel and structurally diverse cationic amphiphiles that mimic the amphiphilic topology of AMPs have recently appeared Many of these compounds exhibit superior pharmacokinetic properties and reduced in vitro toxicity while retaining potent antibacterial activity against resistant and nonresistant bacteria In summary, cationic amphiphiles promise to provide a new and rich source of diverse antibacterial lead structures in the years to come

https://aac.asm.org/content/aac/54/10/4049.full.pdf

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Strategies employed in the design and optimization of synthetic antimicrobial peptide amphiphiles with enhanced therapeutic potentials

2-Aminoimidazoles are an emerging class of small molecules that possess the ability to inhibit and disperse biofilms across bacterial order, class, and phylum. Herein, we report the synergistic effect between a 2-aminoimidazole/triazole conjugate and antibiotics toward dispersing preestablished biofilms, culminating with a 3-orders-of-magnitude increase of biofilm dispersion toward Staphylococcus aureus biofilms. Furthermore, we document that the 2-aminoimidazole/triazole conjugate will also resensitize multidrug-resistant strains of bacteria to the effects of conventional antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii.

Synergistic Effects between Conventional Antibiotics and 2-Aminoimidazole-Derived Antibiofilm Agents

A class of antimicrobial peptides involved in host defense consists of sequences rich in Arg and Trp-R and -W. Analysis of the pharmacophore in these peptides revealed that chains as short as trimers of sequences such as WRW and RWR have antimicrobial activity (M. B. Strom, B. E. Haug, M. L. Skar, W. Stensen, T. Stiberg, and J. S. Svendsen, J. Med. Chem. 46:1567-1570, 2003). To evaluate the effect of chain length on antimicrobial activity, we synthesized a series of peptides containing simple sequence repeats, (RW)n-NH2 (where n equals 1, 2, 3, 4, or 5), and determined their antimicrobial and hemolytic activity. The antimicrobial activity of the peptides increases with chain length, as does the hemolysis of red blood cells. Within the experimental error, longer peptides (n equals 3, 4, or 5) show similar values for the ratio of hemolytic activity to antibacterial activity, or the hemolytic index. The (RW)3 represents the optimal chain length in terms of the efficacy of synthesis and selectivity as evaluated by the hemolytic index. Circular dichroism spectroscopy indicates that these short peptides appear to be unfolded in aqueous solution but acquire structure in the presence of phospholipids. Interaction of the peptides with model lipid vesicles was examined using tryptophan fluorescence. The (RW)n peptides preferentially interact with bilayers containing the negatively charged headgroup phosphatidylglycerol relative to those containing a zwitterionic headgroup, phosphatidylcholine.

Anna Brady

Papers

Length Effects in Antimicrobial Peptides of the (RW)n Series