Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis

Rokeya Tasneen, Si Yang Li, Charles A. Peloquin, Dinesh Taylor, Kathy N. Williams, Koen Andries, Khisimuzi E. Mdluli, Eric L. Nuermberger

Research output: Contribution to journalArticle

Abstract

To truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and isoniazid. On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic. Relapse results were inconclusive due to the low rate of relapse in all test groups. In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone.

Original languageEnglish (US)
Pages (from-to)5485-5492
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume55
Issue number12
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis'. Together they form a unique fingerprint.

  • Cite this