A new antibiotic with potent activity targets MscL

I. Iscla, R. Wray, P. Blount, J. Larkins-Ford, A.L. Conery, F.M. Ausubel, S. Ramu, A. Kavanagh, J.X. Huang, M.A. Blaskovich, M.A. Cooper, A. Obregon-Henao, I. Orme, E.S. Tjandra, U.H. Stroeher, M.H. Brown, C. Macardle, N. Van Holst, C. Ling Tong, A.D. SlatteryC.T. Gibson, C.L. Raston, R.A. Boulos

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    Abstract

    © 2015 Japan Antibiotics Research Association. All rights reserved. The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.
    Original languageEnglish
    Pages (from-to)453-462
    Number of pages10
    JournalJournal of Antibiotics
    Volume68
    Issue number7
    Early online date4 Feb 2015
    DOIs
    Publication statusPublished - Jul 2015

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