title: A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium. kandries@prdbe.jnj.com
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Peter
authors.initials: P
authors.lastname: Verhasselt
authors.forename: Jerome
authors.initials: J
authors.lastname: Guillemont
authors.forename: Hinrich W H
authors.initials: HW
authors.lastname: Göhlmann
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Neefs
authors.forename: Hans
authors.initials: H
authors.lastname: Winkler
authors.forename: Jef
authors.initials: J
authors.lastname: Van Gestel
authors.forename: Philip
authors.initials: P
authors.lastname: Timmerman
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Ennis
authors.initials: E
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Williams
authors.forename: Didier
authors.initials: D
authors.lastname: de Chaffoy
authors.forename: Emma
authors.initials: E
authors.lastname: Huitric
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cambau
authors.forename: Chantal
authors.initials: C
authors.lastname: Truffot-Pernot
authors.forename: Nacer
authors.initials: N
authors.lastname: Lounis
authors.forename: Vincent
authors.initials: V
authors.lastname: Jarlier
mesh_terms: 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
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D011804:Quinolines; C493870:bedaquiline; D025243:Bacterial Proton-Translocating ATPases