1. Academic Validation
  2. In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis

In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis

  • Antimicrob Agents Chemother. 2015 Jan;59(1):136-44. doi: 10.1128/AAC.03823-14.
A M Upton 1 S Cho 2 T J Yang 3 Y Kim 2 Y Wang 2 Y Lu 4 B Wang 4 J Xu 4 K Mdluli 3 Z Ma 3 S G Franzblau 2
Affiliations

Affiliations

  • 1 Global Alliance for TB Drug Development, New York, New York, USA anna.upton@tballiance.org.
  • 2 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
  • 3 Global Alliance for TB Drug Development, New York, New York, USA.
  • 4 Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People's Republic of China.
Abstract

Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10(-7). In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol Infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.

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