Novel antibiotics effective against gram-positive and -negative multi-resistant bacteria with limited resistance

PLoS Biol. 2019 Jul 9;17(7):e3000337. doi: 10.1371/journal.pbio.3000337. eCollection 2019 Jul.

Abstract

Antibiotics are a medical wonder, but an increasing frequency of resistance among most human pathogens is rendering them ineffective. If this trend continues, the consequences for public health and for the general community could be catastrophic. The current clinical pipeline, however, is very limited and is dominated by derivatives of established classes, the "me too" compounds. Here, we have exploited our recent identification of a bacterial toxin to transform it into antibiotics active on multidrug-resistant (MDR) gram-positive and -negative bacterial pathogens. We generated a new family of peptidomimetics-cyclic heptapseudopeptides-inspired from a natural bacterial peptide. Out of the 4 peptides studied, 2 are effective against methicillin-resistant Staphylococcus aureus (MRSA) in mild and severe sepsis mouse models without exhibiting toxicity on human erythrocytes and kidney cells, zebrafish embryos, and mice. These new compounds are safe at their active doses and above, without nephrotoxicity. Efficacy was also demonstrated against Pseudomonas aeruginosa and MRSA in a mouse skin infection model. Importantly, these compounds did not result in resistance after serial passages for 2 weeks and 4 or 6 days' exposure in mice. Activity of heptapseudopeptides was explained by the ability of unnatural amino acids to strengthen dynamic association with bacterial lipid bilayers and to induce membrane permeability, leading to bacterial death. Based on structure determination, we showed that cationic domains surrounded by an extended hydrophobic core could improve bactericidal activity. Because 2 peptide analogs, Pep 16 and Pep19, are effective against both MRSA and P. aeruginosa in severe sepsis and skin infection models, respectively, we believe that these peptidomimetics are promising lead candidates for drug development. We have identified potential therapeutic agents that can provide alternative treatments against antimicrobial resistance. Because the compounds are potential leads for therapeutic development, the next step is to start phase I clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacology*
  • Bacteria / drug effects*
  • Bacteria / growth & development
  • Bacteria / ultrastructure
  • Drug Resistance, Multiple, Bacterial / drug effects
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Methicillin-Resistant Staphylococcus aureus / physiology
  • Mice
  • Microbial Sensitivity Tests / methods
  • Microscopy, Electron, Scanning
  • Microscopy, Electron, Transmission
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / physiology
  • Skin / drug effects*
  • Skin / microbiology
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / microbiology
  • Zebrafish

Substances

  • Anti-Bacterial Agents

Grant support

This research was funded by l’Agence Nationale pour la Recherche (ANR-15-CE12-0003-01, "sRNA-Fit") to BF, la "Fondation pour la Recherche Médicale" (DBF20160635724, "Bactéries et champignons face aux antibiotiques et antifongiques") to BF, and Ouest-Valorisation, Société d’Accélération du Transfert de Technologies to BF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.