In vitro and in vivo activity of clofazimine against Mycobacterium tuberculosis persisters.
OBJECTIVE
To assess the activity of clofazimine (CFZ) against Mycobacterium tuberculosis persisters using an oxygen depletion model and a low-dose aerosol mouse model of chronic tuberculosis (TB).


METHODS
In in vitro experiments, CFZ showed much better activity than isoniazid  under anaerobic conditions. In a low-dose aerosol mouse model of TB, we evaluated the efficacy of CFZ and moxifloxacin at different doses following treatment durations of 30, 60 and 90 days.


RESULTS
CFZ showed significant bactericidal activity in the mouse model over the wide dose range  of 2-200 mg/kg. CFZ activity was dose-dependent. The bacilli were eradicated in the CFZ 200 mg/kg group after treatment for 60 days, and in the CFZ 20 mg/kg group after 90 days of treatment.


CONCLUSIONS
CFZ exhibits dose-dependent, sustained bactericidal activity against M. tuberculosis  persisters, and thus warrants further study to demonstrate its potential to contribute significantly in a novel treatment-shortening regimen.
Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumour Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China.
J
J
Xu
Y
Y
Lu
L
L
Fu
H
H
Zhu
B
B
Wang
K
K
Mdluli
A M
AM
Upton
H
H
Jin
M
M
Zheng
W
W
Zhao
P
P
Li
D000818:Animals; D000995:Antitubercular Agents / Q000097:blood / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology; D002908:Chronic Disease; D002991:Clofazimine / Q000097:blood / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones; D007538:Isoniazid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D011804:Quinolines / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology
D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D002991:Clofazimine; D000077266:Moxifloxacin; D007538:Isoniazid; D012293:Rifampin