@article{3154b909c7a447cdb4e7b4751ee32049,
title = "A new antibiotic with potent activity targets MscL",
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.",
author = "Irene Iscla and Robin Wray and Paul Blount and Jonah Larkins-Ford and Conery, {Annie L.} and Ausubel, {Frederick M.} and Soumya Ramu and Angela Kavanagh and Huang, {Johnny X.} and Blaskovich, {Mark A.} and Cooper, {Matthew A.} and Andres Obregon-Henao and Ian Orme and Tjandra, {Edwin S.} and Stroeher, {Uwe H.} and Brown, {Melissa H.} and Cindy Macardle and {Van Holst}, Nick and {Ling Tong}, Chee and Slattery, {Ashley D.} and Gibson, {Christopher T.} and Raston, {Colin L.} and Boulos, {Ramiz A.}",
note = "Funding Information: The in vivo growth inhibition experiments and the electrophysiology experiments were supported by Grant I-1420 of the Welch Foundation, Grant RP100146 from the Cancer Prevention & Research Institute of Texas, and Grants AI08080701 and GM061028 from the National Institutes of Health. The C. elegans experiments were supported by grant P01 AI083214 from the National Institutes of Health. II is supported by Grant 12SDG8740012 from the National American Heart Association. The funding bodies had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. MAB, JXH, SR and AK were supported by a Wellcome Trust Seeding Drug Discovery Award (094977/Z/10/Z), and MAC by an NHMRC Principal Research Fellowship (APP1059354). UHS is supported by NHMRC Project Grant 535053. We gratefully acknowledge support of this work by the Australian Research Council and the Government of South Australia. RAB gratefully acknowledges supervision from Allan J McKinley during his Honors year when the modeling work was undertaken. SEM analysis was carried out at Adelaide Microscopy and AFM studies were carried out using facilities in the School of Chemical and Physical Sciences, Flinders University. Both of these microscopy facilities are supported by the Australian Microscopy and Microanalysis Research Facility (AMMRF). Flow Cytometry experiments were carried out at Flow Cytometry Immunology facility at Flinders Medical Centre. Ramizol is a Trademark fully registered in Australia. Publisher Copyright: {\textcopyright} 2015 Japan Antibiotics Research Association. All rights reserved.",
year = "2015",
month = jul,
day = "29",
doi = "10.1038/ja.2015.4",
language = "English (US)",
volume = "68",
pages = "453--462",
journal = "Journal of Antibiotics",
issn = "0021-8820",
publisher = "Japan Antibiotics Research Association",
number = "7",
}