A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis

American Association for the Advancement of Science (AAAS) - Tập 307 Số 5707 - Trang 223-227 - 2005
Koen Andries1,2,3,4,5, Peter Verhasselt1,2,3,4,5, Jérôme Guillemont6,1,2,3,5, Hinrich W. H. Göhlmann1,2,3,4,5, Jean‐Marc Neefs1,2,3,4,5, Hans Christian Winkler1,2,3,4,5, Jef Van Gestel1,2,3,4,5, Philip Timmerman1,2,3,4,5, Min Zhu7,1,2,3,5, Ennis Lee1,2,3,4,5, Peter Williams1,2,3,4,5, Didier de Chaffoy1,2,3,4,5, Emma Huitric1,2,3,4,5, Sven Hoffner1,2,3,4,5, Emmanuelle Cambau1,2,3,4,5, C. Truffot-Pernot1,2,3,4,5, Nacer Lounis1,2,3,4,5, Vincent Jarlier1,2,3,4,5
1Johnson & Johnson Pharmaceutical Research & Development, 50–100 Holmers Farm Way, High Wycombe, Bucks HP12 4DP, UK.
2Johnson & Johnson Pharmaceutical Research & Development, 920 Route 202, P.O. Box 300, Raritan, NJ 08869, USA.
3Johnson & Johnson Pharmaceutical Research & Development, Campus de Maigremont-BP615, 27106 Val de Reuil Cedex, France.
4Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
5Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden
6Johnson & Johnson Pharmaceutical Research & Development, Campus de Maigremont-BP615, 27106 Val de Reuil Cedex, France.
7Johnson & Johnson Pharmaceutical Research & Development, 920 Route 202, P.O. Box 300, Raritan, NJ 08869, USA

Tóm tắt

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.

Từ khóa


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We dedicate this paper to the memory of Dr. Paul Janssen who inspired many of us. We thank K. Bush for testing several nonmycobacteria and S. Brown for testing H. pylori ; B. Molenberghs L. Vranckx R. Willebrords T. Gevers P. Janssens H. Szel A. Van Dijck F. Woestenborghs L. Decrane E. Pasquier I. Csoka A. Poncelet D. Vernier and A. Chauffour for technical assistance; B. Neys and P. Leemans for informatics expertise; and the Quintiles group at Guy's Drug Research Unit London who conducted the clinical studies. Portions of the genomic DNA sequencing genome assembly and mutation analysis were performed by 454 Life Sciences Branford CT 06405 USA. The genome sequence for M. smegmatis strain MC2 was licensed from The Institute for Genome Research Rockville MD 20850 USA. The RefSeq accession number for the genomic sequence (including the atpE gene) from M. tuberculosis is NC_000962. The protein sequence of the ATP synthase C chain encoded by atpE gene from M. tuberculosis is Swiss-Prot accession number P63691. The nucleotide sequence of the wild-type atpE gene from M. smegmatis has EMBL accession number AJ862722. See legend to Fig. 2 for more details. Patents pending: EP 04/02402.7 and EP 04/04720.0. Work at the Swedish Institute for Infectious Disease Control and Pitié-Salpêtrière School of Medicine was supported by grants from Johnson & Johnson Pharmaceutical Research and Development. V.J. C.T.-P. N.L. and E.C. are members of the Centre National de Référence de la Résistance des Mycobactéries aux Antituberculeux and they gratefully acknowledge financial support from Association Française Raoul Follereau INSERM (grant EMI 0004) and Ministère de l'Education Nationale et de la Recherche (grant UPRES EA 1541).

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American Association for the Advancement of Science (AAAS)

Tập 307 Số 5707

223-227

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