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Originally published in Science Express on 9 December 2004
Science 14 January 2005:
Vol. 307. no. 5707, pp. 223 - 227
DOI: 10.1126/science.1106753
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Research Articles

A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis

Koen Andries,1* Peter Verhasselt,1 Jerome Guillemont,2 Hinrich W. H. Göhlmann,1 Jean-Marc Neefs,1 Hans Winkler,1 Jef Van Gestel,1 Philip Timmerman,1 Min Zhu,3 Ennis Lee,4 Peter Williams,4 Didier de Chaffoy,1 Emma Huitric,5 Sven Hoffner,5 Emmanuelle Cambau,6 Chantal Truffot-Pernot,6 Nacer Lounis,6{dagger} Vincent Jarlier6

The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 µg/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.

1 Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
2 Johnson & Johnson Pharmaceutical Research & Development, Campus de Maigremont-BP615, 27106 Val de Reuil Cedex, France.
3 Johnson & Johnson Pharmaceutical Research & Development, 920 Route 202, P.O. Box 300, Raritan, NJ 08869, USA.
4 Johnson & Johnson Pharmaceutical Research & Development, 50–100 Holmers Farm Way, High Wycombe, Bucks HP12 4DP, UK.
5 Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden.
6 Pitié-Salpêtrière School of Medicine, University Paris 6, 75634 Paris, France.



{dagger} Present address: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

* To whom correspondence should be addressed. E-mail: kandries{at}prdbe.jnj.com

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