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Published Online December 9, 2004
Science DOI: 10.1126/science.1106753

Research Articles

Submitted on October 26, 2004
Accepted on November 24, 2004

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 Jarlier 6

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, France.

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

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

Tuberculosis has been increasing significantly 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 (MIC 0.06 µg/ml). In mice, R207910 exceeds the bactericidal activities of isoniazid and rifampin by at least 1 log. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid and pyrazinamide) with R207910 accelerates bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibits mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice are well tolerated in healthy human volunteers. Mutants selected in vitro suggest the proton pump of ATP synthase to be the target for the drug.


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Science. ISSN 0036-8075 (print), 1095-9203 (online)