TY - JOUR
T1 - A new antibiotic with potent activity targets MscL
AU - Iscla, Irene
AU - Wray, Robin
AU - Blount, Paul
AU - Larkins-Ford, Jonah
AU - Conery, Annie
AU - Ausubel, Frederick
AU - Ramu, Soumya
AU - Kavanagh, Angela
AU - Huang, Johnny
AU - Blaskovich, Mark
AU - Cooper, Matthew
AU - Obregon-Henao, Andres
AU - Orme, Ian
AU - Tjandra, Edwin
AU - Stroeher, Uwe
AU - Brown, Melissa
AU - Macardle, Peta
AU - VanHolstPellekaan, Nicholas
AU - Tong, Chee Ling
AU - Slattery, Ashley
AU - Gibson, Christopher
AU - Raston, Colin
AU - Boulos, Ramiz
N1 - 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/
PY - 2015/7/29
Y1 - 2015/7/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84938358846&partnerID=8YFLogxK
U2 - 10.1038/ja.2015.4
DO - 10.1038/ja.2015.4
M3 - Article
VL - 68
SP - 453
EP - 462
JO - JOURNAL OF ANTIBIOTICS
JF - JOURNAL OF ANTIBIOTICS
SN - 0021-8820
IS - 7
ER -