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J. Biol. Chem., Vol. 283, Issue 37, 25273-25280, September 12, 2008

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Diarylquinolines Are Bactericidal for Dormant Mycobacteria as a Result of Disturbed ATP Homeostasis^*

Anil Koul¹, Luc Vranckx, Najoua Dendouga, Wendy Balemans, Ilse Van den Wyngaert, Karen Vergauwen, Hinrich W. H. Göhlmann, Rudy Willebrords, Alain Poncelet^¶, Jerome Guillemont^¶, Dirk Bald^||, and Koen Andries

From the Departments of Antimicrobial Research and Functional Genomics, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium, ^¶Pharmaceutical Research and Development, Tibotec NV, Johnson & Johnson, Campus de Maigremont-BP615, F-27106 Val de Reuil Cedex, France, and the ^||Department of Structural Biology, VU University Amsterdam, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands

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.

Received for publication, May 21, 2008 , and in revised form, June 23, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Tibotec NV, Johnson & Johnson, 2340 Beerse, Belgium. Tel.: 32-14-60-34-20; Fax: 32-14-60-54-03; E-mail: akoul{at}prdbe.jnj.com.

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