A <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Cytochrome <italic toggle="yes">bd</italic> Oxidase Mutant Is Hypersensitive to Bedaquiline

ABSTRACT The new medicinal compound bedaquiline (BDQ) kills Mycobacterium tuberculosis by inhibiting F1Fo-ATP synthase. BDQ is bacteriostatic for 4 to 7 days and kills relatively slowly compared to other frontline tuberculosis (TB) drugs. Here we show that killing with BDQ can be improved significan...

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Autores principales:	Michael Berney, Travis E. Hartman, William R. Jacobs
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/69aa159f87974e569df926655462ea6a
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spelling	oai:doaj.org-article:69aa159f87974e569df926655462ea6a2021-11-15T15:47:22ZA <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Cytochrome <italic toggle="yes">bd</italic> Oxidase Mutant Is Hypersensitive to Bedaquiline10.1128/mBio.01275-142150-7511https://doaj.org/article/69aa159f87974e569df926655462ea6a2014-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01275-14https://doaj.org/toc/2150-7511ABSTRACT The new medicinal compound bedaquiline (BDQ) kills Mycobacterium tuberculosis by inhibiting F1Fo-ATP synthase. BDQ is bacteriostatic for 4 to 7 days and kills relatively slowly compared to other frontline tuberculosis (TB) drugs. Here we show that killing with BDQ can be improved significantly by inhibiting cytochrome bd oxidase, a non-proton-pumping terminal oxidase. BDQ was instantly bactericidal against a cytochrome bd oxidase null mutant of M. tuberculosis, and the rate of killing was increased by more than 50%. We propose that this exclusively bacterial enzyme should be a high-priority target for new drug discovery. IMPORTANCE A major drawback of current TB chemotherapy is its long duration. New drug regimens with rapid killing kinetics are desperately needed. Our study demonstrates that inhibition of a nonessential bacterial enzyme greatly improves the efficacy of the latest TB drug bedaquiline and emphasizes that screening for compounds with synergistic killing mechanisms is a promising strategy.Michael BerneyTravis E. HartmanWilliam R. JacobsAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 4 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Michael Berney Travis E. Hartman William R. Jacobs A <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Cytochrome <italic toggle="yes">bd</italic> Oxidase Mutant Is Hypersensitive to Bedaquiline
description	ABSTRACT The new medicinal compound bedaquiline (BDQ) kills Mycobacterium tuberculosis by inhibiting F1Fo-ATP synthase. BDQ is bacteriostatic for 4 to 7 days and kills relatively slowly compared to other frontline tuberculosis (TB) drugs. Here we show that killing with BDQ can be improved significantly by inhibiting cytochrome bd oxidase, a non-proton-pumping terminal oxidase. BDQ was instantly bactericidal against a cytochrome bd oxidase null mutant of M. tuberculosis, and the rate of killing was increased by more than 50%. We propose that this exclusively bacterial enzyme should be a high-priority target for new drug discovery. IMPORTANCE A major drawback of current TB chemotherapy is its long duration. New drug regimens with rapid killing kinetics are desperately needed. Our study demonstrates that inhibition of a nonessential bacterial enzyme greatly improves the efficacy of the latest TB drug bedaquiline and emphasizes that screening for compounds with synergistic killing mechanisms is a promising strategy.
format	article
author	Michael Berney Travis E. Hartman William R. Jacobs
author_facet	Michael Berney Travis E. Hartman William R. Jacobs
author_sort	Michael Berney
title	A <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Cytochrome <italic toggle="yes">bd</italic> Oxidase Mutant Is Hypersensitive to Bedaquiline
title_short	A <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Cytochrome <italic toggle="yes">bd</italic> Oxidase Mutant Is Hypersensitive to Bedaquiline
title_full	A <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Cytochrome <italic toggle="yes">bd</italic> Oxidase Mutant Is Hypersensitive to Bedaquiline
title_fullStr	A <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Cytochrome <italic toggle="yes">bd</italic> Oxidase Mutant Is Hypersensitive to Bedaquiline
title_full_unstemmed	A <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Cytochrome <italic toggle="yes">bd</italic> Oxidase Mutant Is Hypersensitive to Bedaquiline
title_sort	<named-content content-type="genus-species">mycobacterium tuberculosis</named-content> cytochrome <italic toggle="yes">bd</italic> oxidase mutant is hypersensitive to bedaquiline
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/69aa159f87974e569df926655462ea6a
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A <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Cytochrome <italic toggle="yes">bd</italic> Oxidase Mutant Is Hypersensitive to Bedaquiline

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