In vitro and in vivo activity against M. tuberculosis of the nitroimidazole TBA-354

Abstract

Nitroimidazoles are a promising new class of anti-tubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in Phase III trials for treatment of multi-drug resistant tuberculosis while the nitroimidazo-oxazine PA-824 is entering Phase III for drug sensitive and drug resistant tuberculosis. TBA-354 (a.k.a 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 anti-tuberculosis nitroimidazole following an extensive medicinal chemistry effort.

Here, we further evaluate the pharmacokinetic properties and activity against Mycobacterium tuberculosis of TBA-354. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and non-replicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. Addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv-isogenic mono-resistant 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 to delamanid and more potent than PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once daily oral dosing suggest that TBA-354 be studied further for potential as a next generation nitroimidazole.

Citation

Upton, A.M.; Cho, S.; Yang, T.J.; Kim, Y.; Wang, Y.; Lu, Y.; Wang, B.; Xu, J.; Mdluli, K.; Ma, Z.; Franzblau, S.G. In Vitro and In Vivo Activities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy (2015) 59 (1) 136-144. [DOI: 10.1128/AAC.03823-14]

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