title: The diarylquinoline TMC207 for multidrug-resistant tuberculosis.
abstract: BACKGROUND
  The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial ATP synthase. TMC207 potently inhibits drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and shows bactericidal activity in patients who have drug-susceptible pulmonary tuberculosis.
  
  
  METHODS
  In the first stage of a two-stage, phase 2, randomized, controlled trial, we randomly assigned 47 patients who had newly diagnosed multidrug-resistant pulmonary tuberculosis to receive either TMC207 (400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks) (23 patients) or placebo (24 patients) in combination with a standard five-drug, second-line antituberculosis regimen. The primary efficacy end point was the conversion of sputum cultures, in liquid broth, from positive to negative.
  
  
  RESULTS
  The addition of TMC207 to standard therapy for multidrug-resistant tuberculosis reduced the time to conversion to a negative sputum culture, as compared with placebo (hazard ratio, 11.8; 95% confidence interval, 2.3 to 61.3; P=0.003 by Cox regression analysis) and increased the proportion of patients with conversion of sputum culture (48% vs. 9%). The mean log(10) count of colony-forming units in the sputum declined more rapidly in the TMC207 group than in the placebo group. No significant differences in average plasma TMC207 concentrations were noted between patients with and those without culture conversion. Most adverse events were mild to moderate, and only nausea occurred significantly more frequently among patients in the TMC207 group than among patients in the placebo group (26% vs. 4%, P=0.04).
  
  
  CONCLUSIONS
  The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis. (ClinicalTrials.gov number, NCT00449644.)
authors.affiliation: Centre for Clinical Tuberculosis Research, the Department of Science and Technology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, all in South Africa.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
authors.forename: Alexander
authors.initials: A
authors.lastname: Pym
authors.forename: Martin
authors.initials: M
authors.lastname: Grobusch
authors.forename: Ramonde
authors.initials: R
authors.lastname: Patientia
authors.forename: Roxana
authors.initials: R
authors.lastname: Rustomjee
authors.forename: Liesl
authors.initials: L
authors.lastname: Page-Shipp
authors.forename: Christoffel
authors.initials: C
authors.lastname: Pistorius
authors.forename: Rene
authors.initials: R
authors.lastname: Krause
authors.forename: Mampedi
authors.initials: M
authors.lastname: Bogoshi
authors.forename: Gavin
authors.initials: G
authors.lastname: Churchyard
authors.forename: Amour
authors.initials: A
authors.lastname: Venter
authors.forename: Jenny
authors.initials: J
authors.lastname: Allen
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Palomino
authors.forename: Tine
authors.initials: T
authors.lastname: De Marez
authors.forename: Rolf P G
authors.initials: RP
authors.lastname: van Heeswijk
authors.forename: Nacer
authors.initials: N
authors.lastname: Lounis
authors.forename: Paul
authors.initials: P
authors.lastname: Meyvisch
authors.forename: Johan
authors.initials: J
authors.lastname: Verbeeck
authors.forename: Wim
authors.initials: W
authors.lastname: Parys
authors.forename: Karel
authors.initials: K
authors.lastname: de Beule
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: David F
authors.initials: DF
authors.lastname: Mc Neeley
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D064687:Diarylquinolines; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline; D006180:Proton-Translocating ATPases