Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis.
The nitroimidazopyran PA-824 has potent in vitro activity against Mycobacterium tuberculosis, a narrow spectrum of activity limited primarily to the M. tuberculosis complex, and no demonstrable cross-resistance to a variety of antituberculosis drugs. In a series of experiments, we sequentially characterized the activity of PA-824 in an experimental murine model of tuberculosis. The minimal effective dose was 12.5 mg/kg of body weight/day. The minimal bactericidal dose (MBD) was 100 mg/kg/day. When PA-824 was used as monotherapy at the MBD, it exhibited promising bactericidal activity during the initial intensive phase of therapy that was similar to that of the equipotent dose of isoniazid in humans. In combination with isoniazid, PA-824 prevented the selection of isoniazid-resistant mutants. Perhaps more importantly, PA-824 also demonstrated potent activity during the continuation phase of therapy, during which it targeted bacilli that had persisted through an initial 2-month intensive phase of treatment with rifampin, isoniazid, and pyrazinamide. Together, these data strongly support further evaluation of PA-824 in combination with first- or second-line antituberculosis drugs to determine its potential contribution to the treatment of drug-susceptible or multidrug-resistant tuberculosis, respectively.
Tyagi
Sandeep
S
Center for Tuberculosis Research, Johns Hopkins University, 1503 East Jefferson St., Baltimore, MD 21231-1002, USA.
Nuermberger
E
E
Yoshimatsu
T
T
Williams
K
K
Rosenthal
I
I
Lounis
N
N
Bishai
W
W
Grosset
J
J
D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development* / Q000302:isolation & purification; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
D000995:Antitubercular Agents; D009593:Nitroimidazoles; C410767:pretomanid