The diarylquinoline TMC207 for multidrug-resistant tuberculosis.
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.)
Diacon
Andreas H
AH
Centre for Clinical Tuberculosis Research, the Department of Science and Technology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, all in South Africa.
Pym
Alexander
A
Grobusch
Martin
M
Patientia
Ramonde
R
Rustomjee
Roxana
R
Page-Shipp
Liesl
L
Pistorius
Christoffel
C
Krause
Rene
R
Bogoshi
Mampedi
M
Churchyard
Gavin
G
Venter
Amour
A
Allen
Jenny
J
Palomino
Juan Carlos
JC
De Marez
Tine
T
van Heeswijk
Rolf P G
RP
Lounis
Nacer
N
Meyvisch
Paul
P
Verbeeck
Johan
J
Parys
Wim
W
de Beule
Karel
K
Andries
Koen
K
Mc Neeley
David F
DF
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
D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline; D006180:Proton-Translocating ATPases