Andries, Koen; Verhasselt, Peter; Guillemont, Jerome; Goehlmann, Hinrich W. H.; Neefs, Jean-Marc; Winkler, Hans; Van Gestel, Jef; Timmerman, Philip; Zhu, Min; Lee, Ennis; Williams, Peter; de Chaffoy, Didier; Huitric, Emma; Hoffner, Sven; Cambau, Emmanuelle; Truffot-Pernot, Chantal; Lounis, Nacer; Jarlier, Vincent

Science (Washington, DC, United States) (2005), 307(5707), 223-227 CODEN: SCIEAS; ISSN: 0036-8075. English.

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 mo of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 wk. 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 ATP (ATP) synthase.