A new antibiotic with potent activity targets MscL

Irene Iscla, Robin Wray, Paul Blount, Jonah Larkins-Ford, Annie L. Conery, Frederick M. Ausubel, Soumya Ramu, Angela Kavanagh, Johnny X. Huang, Mark A. Blaskovich, Matthew A. Cooper, Andres Obregon-Henao, Ian Orme, Edwin S. Tjandra, Uwe H. Stroeher, Melissa H. Brown, Cindy Macardle, Nick Van Holst, Chee Ling Tong, Ashley D. SlatteryChristopher T. Gibson, Colin L. Raston, Ramiz A. Boulos

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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 (US)
Pages (from-to)453-462
Number of pages10
JournalJournal of Antibiotics
Volume68
Issue number7
DOIs
StatePublished - Jul 29 2015

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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    Iscla, I., Wray, R., Blount, P., Larkins-Ford, J., Conery, A. L., Ausubel, F. M., Ramu, S., Kavanagh, A., Huang, J. X., Blaskovich, M. A., Cooper, M. A., Obregon-Henao, A., Orme, I., Tjandra, E. S., Stroeher, U. H., Brown, M. H., Macardle, C., Van Holst, N., Ling Tong, C., ... Boulos, R. A. (2015). A new antibiotic with potent activity targets MscL. Journal of Antibiotics, 68(7), 453-462. https://doi.org/10.1038/ja.2015.4