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The Discovery of 2‐Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M. tuberculosis to β‐Lactam Antibiotics in a Pattern Distinct from β‐Lactamase Inhibitors
Author(s) -
Nguyen T. Vu,
Blackledge Meghan S.,
Lindsey Erick A.,
Minrovic Bradley M.,
Ackart David F.,
Jeon Albert B.,
ObregónHenao Andrés,
Melander Roberta J.,
Basaraba Randall J.,
Melander Christian
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201612006
Subject(s) - mycobacterium smegmatis , mycobacterium tuberculosis , carbenicillin , antibiotics , microbiology and biotechnology , tuberculosis , lactam , mycobacterium , drug resistance , multiple drug resistance , efflux , biology , chemistry , bacteria , medicine , stereochemistry , ampicillin , biochemistry , genetics , pathology
A library of 2‐aminobenzimidazole derivatives was screened for the ability to suppress β‐lactam resistance in Mycobacterium smegmatis. Several non‐bactericidal compounds were identified that reversed intrinsic resistance to β‐lactam antibiotics in a manner distinct from β‐lactamase inhibitors. Activity also translates to M. tuberculosis, with a lead compound from this study potently suppressing carbenicillin resistance in multiple M. tuberculosis strains (including multidrug‐resistant strains). Preliminary mechanistic studies revealed that the lead compounds act through a mechanism distinct from that of traditional β‐lactamase inhibitors.
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