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Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis

Authors :
Martina Kulén
Christer Larsson
Fredrik Almqvist
K. Syam Krishnan
Erik Chorell
James A. D. Good
Mette R. Hansen
Gregory A. Harrison
Dennis X. Zhu
Jonathan Livny
Scott J. Hultgren
Kelly Flentie
Christina L. Stallings
Anders E. G. Lindgren
Leslie A. Weiss
Torbjörn Wixe
Hasan Tükenmez
Andrew G. Cairns
Christoffer Bengtsson
Souvik Sarkar
Samantha D. Solomon
Miranda E. Schene
Rachel L. Kinsella
Source :
Proceedings of the National Academy of Sciences. 116:10510-10517
Publication Year :
2019
Publisher :
Proceedings of the National Academy of Sciences, 2019.

Abstract

Mycobacterium tuberculosis ( Mtb ) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb , we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Details

ISSN :
10916490 and 00278424
Volume :
116
Database :
OpenAIRE
Journal :
Proceedings of the National Academy of Sciences
Accession number :
edsair.doi...........0fc38cc536017cb4fd2b8f71cbd16357
Full Text :
https://doi.org/10.1073/pnas.1818009116