Publication Date:
2004-12-14
Description:
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 mug/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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Andries, Koen -- Verhasselt, Peter -- Guillemont, Jerome -- Gohlmann, 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 -- New York, N.Y. -- Science. 2005 Jan 14;307(5707):223-7. Epub 2004 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium. kandries@prdbe.jnj.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15591164" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Animals
;
Antitubercular Agents/chemistry/pharmacokinetics/*pharmacology/therapeutic use
;
Bacterial Proton-Translocating ATPases/*antagonists &
;
inhibitors/chemistry/metabolism
;
Diarylquinolines
;
Dose-Response Relationship, Drug
;
Drug Evaluation, Preclinical
;
Drug Resistance, Bacterial
;
Drug Therapy, Combination
;
Enzyme Inhibitors/chemistry/pharmacology/therapeutic use
;
Humans
;
Male
;
Mice
;
Microbial Sensitivity Tests
;
Molecular Sequence Data
;
Mycobacterium smegmatis/drug effects/enzymology/growth & development
;
Mycobacterium tuberculosis/*drug effects/enzymology/growth & development
;
Point Mutation
;
Protein Subunits/antagonists & inhibitors/chemistry
;
Quinolines/chemistry/pharmacokinetics/*pharmacology/*therapeutic use
;
Tuberculosis/*drug therapy/microbiology
;
Tuberculosis, Multidrug-Resistant/drug therapy/microbiology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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