Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/103384
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Type: Journal article
Title: A new antibiotic with potent activity targets MscL
Author: Iscla, I.
Wray, R.
Blount, P.
Larkins-Ford, J.
Conery, A.
Ausubel, F.
Ramu, S.
Kavanagh, A.
Huang, J.
Blaskovich, M.
Cooper, M.
Obregon-Henao, A.
Orme, I.
Tjandra, E.
Stroeher, U.
Brown, M.
Macardle, C.
van Holst Pellekaan, N.
Ling Tong, C.
Slattery, A.
et al.
Citation: Journal of Antibiotics: an international journal devoted to research on bioactive microbial products, 2015; 68(7):453-462
Publisher: Japan Antibiotics Research Association
Issue Date: 2015
ISSN: 0021-8820
1881-1469
Statement of
Responsibility: 
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 Slattery, Christopher T Gibson, Colin L Raston and Ramiz A Boulos
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.
Keywords: Cell Line
Animals
Humans
Caenorhabditis elegans
Staphylococcal Infections
Disease Models, Animal
Ion Channels
Enzyme Inhibitors
Anti-Bacterial Agents
Treatment Outcome
Microbial Sensitivity Tests
Mechanotransduction, Cellular
Methicillin-Resistant Staphylococcus aureus
Rights: © 2015 Japan Antibiotics Research Association All rights reserved. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
DOI: 10.1038/ja.2015.4
Grant ID: http://purl.org/au-research/grants/nhmrc/1059354
http://purl.org/au-research/grants/nhmrc/535053
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