Diarylquinolines Are Bactericidal for Dormant Mycobacteria as a Result of Disturbed ATP Homeostasis
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 A...
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| Veröffentlicht in: | The Journal of biological chemistry 2008-09, Vol.283 (37), p.25273-25280 |
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| creator | Koul, Anil Vranckx, Luc Dendouga, Najoua Balemans, Wendy Van den Wyngaert, Ilse Vergauwen, Karen Göhlmann, Hinrich W.H. Willebrords, Rudy Poncelet, Alain Guillemont, Jerome Bald, Dirk Andries, Koen |
| description | 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. |
| doi_str_mv | 10.1074/jbc.M803899200 |
| format | Article |
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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.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M803899200</identifier><identifier>PMID: 18625705</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenosine Triphosphate - chemistry ; Antitubercular Agents - pharmacology ; Gene Expression Regulation, Bacterial ; Homeostasis ; Mitochondrial Proton-Translocating ATPases - chemistry ; Models, Biological ; Mycobacterium - metabolism ; Mycobacterium bovis - drug effects ; Mycobacterium bovis - metabolism ; Mycobacterium smegmatis - drug effects ; Mycobacterium smegmatis - metabolism ; Mycobacterium tuberculosis - drug effects ; Mycobacterium tuberculosis - metabolism ; Nitric Oxide - chemistry ; Oxygen - chemistry ; Quinolines - pharmacology ; RNA, Messenger - metabolism ; Time Factors</subject><ispartof>The Journal of biological chemistry, 2008-09, Vol.283 (37), p.25273-25280</ispartof><rights>2008 © 2008 ASBMB. 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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. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Adenosine Triphosphate - chemistry Antitubercular Agents - pharmacology Gene Expression Regulation, Bacterial Homeostasis Mitochondrial Proton-Translocating ATPases - chemistry Models, Biological Mycobacterium - metabolism Mycobacterium bovis - drug effects Mycobacterium bovis - metabolism Mycobacterium smegmatis - drug effects Mycobacterium smegmatis - metabolism Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - metabolism Nitric Oxide - chemistry Oxygen - chemistry Quinolines - pharmacology RNA, Messenger - metabolism Time Factors |
| title | Diarylquinolines Are Bactericidal for Dormant Mycobacteria as a Result of Disturbed ATP Homeostasis |
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