Chemical disarming of isoniazid resistance in <i>Mycobacterium tuberculosis</i>

Abstract

<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) 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 <i>Mtb</i> 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 <i>Mtb</i>, 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 <i>Mtb</i> strains harboring mutations in the <i>katG</i> gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits <i>Mtb</i> respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect <i>Mtb</i> persistence, we discovered that INH resistance is not absolute and can be reversed.