A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.
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.
Andries
Koen
K
Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium. kandries@prdbe.jnj.com
Verhasselt
Peter
P
Guillemont
Jerome
J
Göhlmann
Hinrich W H
HW
Neefs
Jean-Marc
JM
Winkler
Hans
H
Van Gestel
Jef
J
Timmerman
Philip
P
Zhu
Min
M
Lee
Ennis
E
Williams
Peter
P
de Chaffoy
Didier
D
Huitric
Emma
E
Hoffner
Sven
S
Cambau
Emmanuelle
E
Truffot-Pernot
Chantal
C
Lounis
Nacer
N
Jarlier
Vincent
V
D000595:Amino Acid Sequence; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D025243:Bacterial Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D064687:Diarylquinolines; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D017354:Point Mutation; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology
D000995:Antitubercular Agents; D064687:Diarylquinolines; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D011804:Quinolines; C493870:bedaquiline; D025243:Bacterial Proton-Translocating ATPases