The Isoniazid Paradigm of Killing, Resistance, and Persistence in Mycobacterium tuberculosis

Journal of Molecular Biology
Catherine Vilchèze, William R Jacobs

Abstract

Isoniazid (INH) was the first synthesized drug that mediated bactericidal killing of the bacterium Mycobacterium tuberculosis, a major clinical breakthrough. To this day, INH remains a cornerstone of modern tuberculosis (TB) chemotherapy. This review describes the serendipitous discovery of INH, its effectiveness on TB patients, and early studies to discover its mechanisms of bacteriocidal activity. Forty years after its introduction as a TB drug, the development of gene transfer in mycobacteria enabled the discovery of the genes encoding INH resistance, namely, the activator (katG) and the target (inhA) of INH. Further biochemical and x-ray crystallography studies on KatG and InhA proteins and mutants provided comprehensive understanding of INH mode of action and resistance mechanisms. Bacterial cultures can harbor subpopulations that are genetically or phenotypically resistant cells, the latter known as persisters. Treatment of exponentially growing cultures of M. tuberculosis with INH reproducibly kills 99% to 99.9% of cells in 3 days. Importantly, the surviving cells are slowly replicating or non-replicating cells expressing a unique stress response signature: these are the persisters. These persisters can be visualized usi...Continue Reading

Citations

Jun 26, 2020·Dalton Transactions : an International Journal of Inorganic Chemistry·Luiz G F LopesEduardo H S Sousa
Feb 8, 2020·Proceedings of the National Academy of Sciences of the United States of America·Suzanne M Hingley-WilsonJohnjoe McFadden
Jun 26, 2020·Science Translational Medicine·Sarah M SchraderCarl Nathan
Nov 16, 2019·Scientific Reports·Meta A SimonSuryadi Ismadji
Dec 19, 2020·Pharmaceuticals·Daria RóżyckaAgnieszka B Olejniczak
Dec 16, 2020·FEMS Microbiology Reviews·Rhastin A D CastroSebastien Gagneux
Nov 19, 2019·Progress in Biophysics and Molecular Biology·Ludovica Mascolo, Dirk Bald
Mar 7, 2021·Clinical Pharmacokinetics·Marieke G G SturkenboomJan-Willem C Alffenaar
Feb 23, 2021·Frontiers in Microbiology·Anna Allué-GuardiaJordi B Torrelles
Feb 28, 2021·Chemical Biology & Drug Design·Shahinda S R AlsayedHendra Gunosewoyo
Mar 26, 2021·Frontiers in Molecular Biosciences·Monica Civera, Sara Sattin
Apr 8, 2021·Microbiology·Leah Isobella Rankine-WilsonYossef Av-Gay
Jul 1, 2021·Chemical Reviews·Mira HolzheimerAdriaan J Minnaard
Aug 7, 2021·FEMS Microbiology Reviews·J UrbaniecJ McFadden
Oct 5, 2021·Lipids in Health and Disease·Daniel MekonnenAbraham Aseffa

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antitubercular Agents

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

Antitubercular Agents (ASM)

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

Related Papers

The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union Against Tuberculosis and Lung Disease
P DobnerH Rinder
Proceedings of the National Academy of Sciences of the United States of America
Catherine VilchèzeWilliam R Jacobs
Antimicrobial Agents and Chemotherapy
Wing Wai YewYing Zhang
Journal of Microbiology, Immunology, and Infection = Wei Mian Yu Gan Ran Za Zhi
Shu-Ting TsengZhi-Yuan Shi
© 2022 Meta ULC. All rights reserved