Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Science Signaling - Call for Papers

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

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
Prev | Table of Contents | Next

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Trends in Tuberculosis--United States, 2007.
(2008)
JAMA 299, 2142-2144
   Full Text »    PDF »
Short read fragment assembly of bacterial genomes.
M. J. Chaisson and P. A. Pevzner (2008)
Genome Res. 18, 324-330
   Abstract »    Full Text »    PDF »
Characterization of the Mycobacterium tuberculosis 4-Diphosphocytidyl-2-C-Methyl-D-Erythritol Synthase: Potential for Drug Development.
H. Eoh, A. C. Brown, L. Buetow, W. N. Hunter, T. Parish, D. Kaur, P. J. Brennan, and D. C. Crick (2007)
J. Bacteriol. 189, 8922-8927
   Abstract »    Full Text »    PDF »
Tuberculosis and its future management.
J. C Moore-Gillon (2007)
Thorax 62, 1019-1021
   Full Text »    PDF »
The Alanine Racemase of Mycobacterium smegmatis Is Essential for Growth in the Absence of D-Alanine.
D. L. Milligan, S. L. Tran, U. Strych, G. M. Cook, and K. L. Krause (2007)
J. Bacteriol. 189, 8381-8386
   Abstract »    Full Text »    PDF »
In Vitro Antimycobacterial Spectrum of a Diarylquinoline ATP Synthase Inhibitor.
E. Huitric, P. Verhasselt, K. Andries, and S. E. Hoffner (2007)
Antimicrob. Agents Chemother. 51, 4202-4204
   Abstract »    Full Text »    PDF »
Location of Persisting Mycobacteria in a Guinea Pig Model of Tuberculosis Revealed by R207910.
A. J. Lenaerts, D. Hoff, S. Aly, S. Ehlers, K. Andries, L. Cantarero, I. M. Orme, and R. J. Basaraba (2007)
Antimicrob. Agents Chemother. 51, 3338-3345
   Abstract »    Full Text »    PDF »
Novel Links between Antibiotic Resistance and Antibiotic Production.
J. R. Nodwell (2007)
J. Bacteriol. 189, 3683-3685
   Full Text »    PDF »
Antimycobacterial activity of bacteriocins and their complexes with liposomes.
V. Sosunov, V. Mischenko, B. Eruslanov, E. Svetoch, Y. Shakina, N. Stern, K. Majorov, G. Sorokoumova, A. Selishcheva, and A. Apt (2007)
J. Antimicrob. Chemother. 59, 919-925
   Abstract »    Full Text »    PDF »
Drug Therapy of Experimental Tuberculosis (TB): Improved Outcome by Combining SQ109, a New Diamine Antibiotic, with Existing TB Drugs.
B. V. Nikonenko, M. Protopopova, R. Samala, L. Einck, and C. A. Nacy (2007)
Antimicrob. Agents Chemother. 51, 1563-1565
   Abstract »    Full Text »    PDF »
Synergistic Activity of R207910 Combined with Pyrazinamide against Murine Tuberculosis.
M. Ibrahim, K. Andries, N. Lounis, A. Chauffour, C. Truffot-Pernot, V. Jarlier, and N. Veziris (2007)
Antimicrob. Agents Chemother. 51, 1011-1015
   Abstract »    Full Text »    PDF »
An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases.
D. E. Griffith, T. Aksamit, B. A. Brown-Elliott, A. Catanzaro, C. Daley, F. Gordin, S. M. Holland, R. Horsburgh, G. Huitt, M. F. Iademarco, et al. (2007)
Am. J. Respir. Crit. Care Med. 175, 367-416
   Full Text »    PDF »
MDR-TB AND HIV: THE PERFECT STORM?.
J. FIERER (2006)
Am J Trop Med Hyg 75, 1025-1026
   Full Text »    PDF »
In Vitro Activities of the Novel Oxazolidinones DA-7867 and DA-7157 against Rapidly and Slowly Growing Mycobacteria.
L. Vera-Cabrera, B. A. Brown-Elliott, R. J. Wallace Jr., J. Ocampo-Candiani, O. Welsh, S. H. Choi, and C. A. Molina-Torres (2006)
Antimicrob. Agents Chemother. 50, 4027-4029
   Abstract »    Full Text »    PDF »
Effects of weak acids, UV and proton motive force inhibitors on pyrazinamide activity against Mycobacterium tuberculosis in vitro.
M. M. Wade and Y. Zhang (2006)
J. Antimicrob. Chemother. 58, 936-941
   Abstract »    Full Text »    PDF »
Combinations of R207910 with Drugs Used To Treat Multidrug-Resistant Tuberculosis Have the Potential To Shorten Treatment Duration.
N. Lounis, N. Veziris, A. Chauffour, C. Truffot-Pernot, K. Andries, and V. Jarlier (2006)
Antimicrob. Agents Chemother. 50, 3543-3547
   Abstract »    Full Text »    PDF »
Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis.
I-N. Park, S.-B. Hong, Y.-M. Oh, M.-N. Kim, C.-M. Lim, S. D. Lee, Y. Koh, W. S. Kim, D. S. Kim, W. D. Kim, et al. (2006)
J. Antimicrob. Chemother. 58, 701-704
   Abstract »    Full Text »    PDF »
Genetic basis for natural and acquired resistance to the diarylquinoline r207910 in mycobacteria..
S. Petrella, E. Cambau, A. Chauffour, K. Andries, V. Jarlier, and W. Sougakoff (2006)
Antimicrob. Agents Chemother. 50, 2853-2856
   Abstract »    Full Text »    PDF »
Multidrug-resistant tuberculosis: a menace that threatens to destabilize tuberculosis control..
S. K. Sharma and A. Mohan (2006)
Chest 130, 261-272
   Abstract »    Full Text »    PDF »
In Vitro and In Vivo Activities of Rifampin, Streptomycin, Amikacin, Moxifloxacin, R207910, Linezolid, and PA-824 against Mycobacterium ulcerans..
B. Ji, S. Lefrancois, J. Robert, A. Chauffour, C. Truffot, and V. Jarlier (2006)
Antimicrob. Agents Chemother. 50, 1921-1926
   Abstract »    Full Text »    PDF »
The crystal structure of Mycobacterium tuberculosis adenylate kinase in complex with two molecules of ADP and Mg2+ supports an associative mechanism for phosphoryl transfer.
M. Bellinzoni, A. Haouz, M. Grana, H. Munier-Lehmann, W. Shepard, and P. M. Alzari (2006)
Protein Sci. 15, 1489-1493
   Abstract »    Full Text »    PDF »
Bactericidal Activities of R207910 and Other Newer Antimicrobial Agents against Mycobacterium leprae in Mice..
B. Ji, A. Chauffour, K. Andries, and V. Jarlier (2006)
Antimicrob. Agents Chemother. 50, 1558-1560
   Abstract »    Full Text »    PDF »
Application of sequence-based methods in human microbial ecology.
L. Weng, E. M. Rubin, and J. Bristow (2006)
Genome Res. 16, 316-322
   Abstract »    Full Text »    PDF »
Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines.
M. Protopopova, C. Hanrahan, B. Nikonenko, R. Samala, P. Chen, J. Gearhart, L. Einck, and C. A. Nacy (2005)
J. Antimicrob. Chemother. 56, 968-974
   Abstract »    Full Text »    PDF »
Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization.
D. T. Hung, E. A. Shakhnovich, E. Pierson, and J. J. Mekalanos (2005)
Science 310, 670-674
   Abstract »    Full Text »    PDF »
Changes in energy metabolism of Mycobacterium tuberculosis in mouse lung and under in vitro conditions affecting aerobic respiration.
L. Shi, C. D. Sohaskey, B. D. Kana, S. Dawes, R. J. North, V. Mizrahi, and M. L. Gennaro (2005)
PNAS 102, 15629-15634
   Abstract »    Full Text »    PDF »
In Vitro Susceptibility of Mycobacterium tuberculosis Clinical Isolates to Garenoxacin and DA-7867.
L. Vera-Cabrera, J. Castro-Garza, A. Rendon, J. Ocampo-Candiani, O. Welsh, S. H. Choi, K. Blackwood, and C. Molina-Torres (2005)
Antimicrob. Agents Chemother. 49, 4351-4353
   Abstract »    Full Text »    PDF »
Effect of subinhibitory concentrations of ciprofloxacin on Mycobacterium fortuitum mutation rates.
S. H. Gillespie, S. Basu, A. L. Dickens, D. M. O'Sullivan, and T. D. McHugh (2005)
J. Antimicrob. Chemother. 56, 344-348
   Abstract »    Full Text »    PDF »
Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: Identification of {alpha}-ketoglutarate decarboxylase.
J. Tian, R. Bryk, M. Itoh, M. Suematsu, and C. Nathan (2005)
PNAS 102, 10670-10675
   Abstract »    Full Text »    PDF »
Novel Approach to Mapping of Resistance Mutations in Whole Genomes by Using Restriction Enzyme Modulation of Transformation Efficiency.
C. G. Lerner, S. J. Kakavas, C. Wagner, R. T. Chang, P. J. Merta, X. Ruan, R. E. Metzger, and B. A. Beutel (2005)
Antimicrob. Agents Chemother. 49, 2767-2777
   Abstract »    Full Text »    PDF »
Evolution of Tuberculosis Control and Prospects for Reducing Tuberculosis Incidence, Prevalence, and Deaths Globally.
C. Dye, C. J. Watt, D. M. Bleed, S. M. Hosseini, and M. C. Raviglione (2005)
JAMA 293, 2767-2775
   Abstract »    Full Text »    PDF »
Update on the Treatment of Tuberculosis and Latent Tuberculosis Infection.
H. M. Blumberg, M. K. Leonard Jr, and R. M. Jasmer (2005)
JAMA 293, 2776-2784
   Abstract »    Full Text »    PDF »
Multidrug-Resistant Tuberculosis: News From the Front.
M. D. Nettleman (2005)
JAMA 293, 2788-2790
   Full Text »    PDF »
New Small-Molecule Synthetic Antimycobacterials.
L. Ballell, R. A. Field, K. Duncan, and R. J. Young (2005)
Antimicrob. Agents Chemother. 49, 2153-2163
   Full Text »    PDF »
A new class of antimycobacterial drugs: the diarylquinolines.
I Samson (2005)
Thorax 60, 495
   Full Text »    PDF »
Structure of the Rotor Ring of F-Type Na+-ATPase from Ilyobacter tartaricus.
T. Meier, P. Polzer, K. Diederichs, W. Welte, and P. Dimroth (2005)
Science 308, 659-662
   Abstract »    Full Text »    PDF »
Toward a New Therapy for Tuberculosis.
E. J. Rubin (2005)
N. Engl. J. Med. 352, 933-934
   Full Text »    PDF »
Powerful New TB Drug.
(2005)
Journal Watch (General) 2005, 4
   Full Text »


ADVERTISEMENT
Click Me!

ADVERTISEMENT
Click Me!

To Advertise     Find Products