Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis.

A. Koul, L. Vranckx, N. Dendouga, W. Balemans, I van den Wyngaert, K Vergauwen, H.W.H. Goehlmann, R. Willebrords, A Poncelet, J. Guillemont, D. Bald, K. Andries

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

An estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. These nonreplicating, dormant bacilli are tolerant to conventional anti-tuberculosis drugs, such as isoniazid. We recently identified diarylquinoline R207910 (also called TMC207) as an inhibitor of ATP synthase with a remarkable activity against replicating mycobacteria. In the present study, we show that R207910 kills dormant bacilli as effectively as aerobically grown bacilli with the same target specificity. Despite a transcriptional down-regulation of the ATP synthase operon and significantly lower cellular ATP levels, we show that dormant mycobacteria do possess residual ATP synthase enzymatic activity. This activity is blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect. We conclude that this residual ATP synthase activity is indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguishes them entirely from the current anti-tuberculosis drugs and underlines the potential of R207910 to shorten tuberculosis treatment. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
Original languageEnglish
Pages (from-to)25273-25280
JournalJournal of Biological Chemistry
Volume283
DOIs
Publication statusPublished - 2008

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Diarylquinolines
bedaquiline
Mycobacterium
Homeostasis
Adenosine Triphosphate
Bacilli
Bacillus
Tuberculosis
Pharmaceutical Preparations
Isoniazid
Operon
Mycobacterium tuberculosis
Down-Regulation

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Koul, A., Vranckx, L., Dendouga, N., Balemans, W., van den Wyngaert, I., Vergauwen, K., ... Andries, K. (2008). Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. Journal of Biological Chemistry, 283, 25273-25280. https://doi.org/10.1074/jbc.M803899200
Koul, A. ; Vranckx, L. ; Dendouga, N. ; Balemans, W. ; van den Wyngaert, I ; Vergauwen, K ; Goehlmann, H.W.H. ; Willebrords, R. ; Poncelet, A ; Guillemont, J. ; Bald, D. ; Andries, K. / Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. In: Journal of Biological Chemistry. 2008 ; Vol. 283. pp. 25273-25280.
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Koul, A, Vranckx, L, Dendouga, N, Balemans, W, van den Wyngaert, I, Vergauwen, K, Goehlmann, HWH, Willebrords, R, Poncelet, A, Guillemont, J, Bald, D & Andries, K 2008, 'Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis.' Journal of Biological Chemistry, vol. 283, pp. 25273-25280. https://doi.org/10.1074/jbc.M803899200

Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. / Koul, A.; Vranckx, L.; Dendouga, N.; Balemans, W.; van den Wyngaert, I; Vergauwen, K; Goehlmann, H.W.H.; Willebrords, R.; Poncelet, A; Guillemont, J.; Bald, D.; Andries, K.

In: Journal of Biological Chemistry, Vol. 283, 2008, p. 25273-25280.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis.

AU - Koul, A.

AU - Vranckx, L.

AU - Dendouga, N.

AU - Balemans, W.

AU - van den Wyngaert, I

AU - Vergauwen, K

AU - Goehlmann, H.W.H.

AU - Willebrords, R.

AU - Poncelet, A

AU - Guillemont, J.

AU - Bald, D.

AU - Andries, K.

PY - 2008

Y1 - 2008

N2 - An estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. These nonreplicating, dormant bacilli are tolerant to conventional anti-tuberculosis drugs, such as isoniazid. We recently identified diarylquinoline R207910 (also called TMC207) as an inhibitor of ATP synthase with a remarkable activity against replicating mycobacteria. In the present study, we show that R207910 kills dormant bacilli as effectively as aerobically grown bacilli with the same target specificity. Despite a transcriptional down-regulation of the ATP synthase operon and significantly lower cellular ATP levels, we show that dormant mycobacteria do possess residual ATP synthase enzymatic activity. This activity is blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect. We conclude that this residual ATP synthase activity is indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguishes them entirely from the current anti-tuberculosis drugs and underlines the potential of R207910 to shorten tuberculosis treatment. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

AB - An estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. These nonreplicating, dormant bacilli are tolerant to conventional anti-tuberculosis drugs, such as isoniazid. We recently identified diarylquinoline R207910 (also called TMC207) as an inhibitor of ATP synthase with a remarkable activity against replicating mycobacteria. In the present study, we show that R207910 kills dormant bacilli as effectively as aerobically grown bacilli with the same target specificity. Despite a transcriptional down-regulation of the ATP synthase operon and significantly lower cellular ATP levels, we show that dormant mycobacteria do possess residual ATP synthase enzymatic activity. This activity is blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect. We conclude that this residual ATP synthase activity is indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguishes them entirely from the current anti-tuberculosis drugs and underlines the potential of R207910 to shorten tuberculosis treatment. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

U2 - 10.1074/jbc.M803899200

DO - 10.1074/jbc.M803899200

M3 - Article

VL - 283

SP - 25273

EP - 25280

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

ER -