![]() Received: ApAccepted: JPublished: July 9, 2019Ĭopyright: © 2019 Nicolas et al. ![]() PLoS Biol 17(7):Īcademic Editor: Csaba Pál, Biological Research Center, HUNGARY Because the compounds are potential leads for therapeutic development, the next step is to start phase I clinical trials.Ĭitation: Nicolas I, Bordeau V, Bondon A, Baudy-Floc’h M, Felden B (2019) Novel antibiotics effective against gram-positive and -negative multi-resistant bacteria with limited resistance. We have identified potential therapeutic agents that can provide alternative treatments against antimicrobial resistance. aeruginosa in severe sepsis and skin infection models, respectively, we believe that these peptidomimetics are promising lead candidates for drug development. Because 2 peptide analogs, Pep 16 and Pep19, are effective against both MRSA and P. Based on structure determination, we showed that cationic domains surrounded by an extended hydrophobic core could improve bactericidal activity. 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. Importantly, these compounds did not result in resistance after serial passages for 2 weeks and 4 or 6 days’ exposure in mice. Efficacy was also demonstrated against Pseudomonas aeruginosa and MRSA in a mouse skin infection model. These new compounds are safe at their active doses and above, without nephrotoxicity. 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. We generated a new family of peptidomimetics-cyclic heptapseudopeptides-inspired from a natural bacterial peptide. 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. The current clinical pipeline, however, is very limited and is dominated by derivatives of established classes, the “me too” compounds. If this trend continues, the consequences for public health and for the general community could be catastrophic. Antibiotics are a medical wonder, but an increasing frequency of resistance among most human pathogens is rendering them ineffective.
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