Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug resistant Mycobacterium tuberculosis .

Autor:	Harrison GA; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, Saint Louis, MO, USA., Cho K; Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA.; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO USA., Wang ER; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, Saint Louis, MO, USA., Sarkar S; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden., Almqvist F; Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.; Umeå Centre for Microbial Research, UCMR, Umeå University, SE-90187 Umeå, Sweden., Patti GJ; Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA.; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO USA., Stallings CL; Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, Saint Louis, MO, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 07. Date of Electronic Publication: 2023 Feb 07.
DOI:	10.1101/2023.02.06.527416
Abstrakt:	Of the approximately 10 million cases of Mycobacterium tuberculosis ( Mtb ) infections each year, over 10% are resistant to the frontline antibiotic isoniazid (INH). INH resistance is predominantly caused by mutations that decrease the activity of the bacterial enzyme KatG, which mediates conversion of the pro-drug INH to its active form INH-NAD. We previously discovered an inhibitor of Mtb respiration, C10, that enhances the bactericidal activity of INH, prevents the emergence of INH-resistant mutants, and re-sensitizes a collection of INH-resistant mutants to INH through an unknown mechanism. To investigate the mechanism of action of C10, we exploited the toxicity of high concentrations of C10 to select for resistant mutants. We discovered two mutations that confer resistance to the disruption of energy metabolism and allow for growth of Mtb in high C10 concentrations, indicating that growth inhibition by C10 is associated with inhibition of respiration. Using these mutants as well as direct inhibitors of the Mtb electron transport chain, we provide evidence that inhibition of energy metabolism by C10 is neither sufficient nor necessary to potentiate killing by INH. Instead, we find that C10 acts downstream of INH-NAD synthesis, causing Mtb to become particularly sensitive to inhibition of the INH-NAD target, InhA, without changing the concentration of INH-NAD or the activity of InhA, the two predominant mechanisms of potentiating INH. Our studies revealed that there exists a vulnerability in Mtb that can be exploited to render Mtb sensitive to otherwise subinhibitory concentrations of InhA inhibitor. Competing Interests: Competing Interests The authors have no competing financial interests to declare, but acknowledge that C.L.S. and F.A. have ownership in the company QureTech Bio AB that licenses C10 and, therefore, may financially benefit if the company is successful in marketing its product, and the Patti laboratory has a research collaboration agreement with Agilent Technologies.
Databáze:	MEDLINE
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