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dc.contributor.authorLee, Bei Shi
dc.contributor.authorHards, Kiel
dc.contributor.authorEngelhart, Curtis A.
dc.contributor.authorHasenoehrl, Erik J.
dc.contributor.authorKalia, Nitin P.
dc.contributor.authorMackenzie, Jared S.
dc.contributor.authorSviriaeva, Ekaterina
dc.contributor.authorChong, Shi Min Sherilyn
dc.contributor.authorManimekalai, Sony S.
dc.contributor.authorKoh, Vanessa H.
dc.contributor.authorXu, Jiayong
dc.contributor.authorAlonso, Sylvie
dc.contributor.authorMiller, Marvin J.
dc.contributor.authorSteyn, Adrie J.C.
dc.contributor.authorGruber, Gerhard
dc.contributor.authorSchnappinger, Dirk
dc.contributor.authorBerney, Michael
dc.contributor.authorCook, Gregory M.
dc.contributor.authorMoraski, Garrett C.
dc.contributor.authorPethe, Kevin
dc.identifier.citationLee, B. S., Hards, K., Engelhart, C. A., Hasenoehrl, E. J., Kalia, N. P., Mackenzie, J. S., ... & Pethe, K. (2021). Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis. EMBO molecular medicine, 13(1), e13207.en_US
dc.description.abstractThe approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F1F0 ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from Q203-induced death, highlighting the attractiveness of the bd-type terminal oxidase for drug development. Here, we employed a facile whole-cell screen approach to identify the cytochrome bd inhibitor ND-011992. Although ND-011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotictolerant, non-replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment.en_US
dc.titleDual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosisen_US
mus.citation.journaltitleEMBO Molecular Medicineen_US
mus.relation.collegeCollege of Letters & Scienceen_US
mus.relation.departmentChemistry & Biochemistry.en_US
mus.relation.universityMontana State University - Bozemanen_US

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