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

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.

• Authors: A M Upton, S Cho, T J Yang, Y Kim, Y Wang, Y Lu, B Wang, J Xu, K Mdluli, Z Ma, S G Franzblau
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 1 Pg. 136-44 (Jan 2015) ISSN: 1098-6596 [Electronic] United States
• PMID: 25331696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antitubercular Agents
• Nitroimidazoles
• OPC-67683
• Oxazines
• Oxazoles
• TBA-354
• pretomanid

Topics

• Animals
• Antitubercular Agents (pharmacokinetics, therapeutic use)
• Caco-2 Cells
• Cell Line, Tumor
• Disease Models, Animal
• Drug Interactions
• Drug Resistance, Bacterial (genetics)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects)
• Nitroimidazoles (pharmacokinetics, therapeutic use)
• Oxazines (pharmacokinetics, therapeutic use)
• Oxazoles (therapeutic use)
• Tuberculosis (drug therapy)