Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis

TY - JOUR

T1 - Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis

AU - Flentie, Kelly

AU - Harrison, Gregory A.

AU - Tükenmez, Hasan

AU - Livny, Jonathan

AU - Good, James A .D.

AU - Sarkar, Souvik

AU - Zhu, Dennis X.

AU - Kinsella, Rachel L.

AU - Weiss, Leslie A.

AU - Solomon, Samantha D.

AU - Schene, Miranda E.

AU - Hansen, Mette R.

AU - Cairns, Andrew G.

AU - Kulén, Martina

AU - Wixe, Torbjörn

AU - Lindgren, Anders E. G.

AU - Chorell, Erik

AU - Bengtsson, Christoffer

AU - Krishnan, K. Syam

AU - Hultgren, Scott J.

AU - Larsson, Christer

AU - Almqvist, Fredrik

AU - Stallings, Christina L.

PY - 2019/5/21

Y1 - 2019/5/21

N2 - 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.

AB - 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.

KW - antibiotic resistance

KW - drug tolerance

KW - isoniazid

KW - Mycobacterium tuberculosis

KW - respiration

UR - https://www.scopus.com/pages/publications/85066100071

U2 - 10.1073/pnas.1818009116

DO - 10.1073/pnas.1818009116

M3 - Article

C2 - 31061116

AN - SCOPUS:85066100071

SN - 0027-8424

VL - 116

SP - 10510

EP - 10517

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 21

ER -