TBA354

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Background

TBA354 is a new antitubercular agent [1]. TBA354 is a pyridine-containing biaryl compound against Mycobacterium tuberculosis. In 10 M. tuberculosis strains tested, the MIC range for TBA-354 was <0.02 to 0.36 μM. The MICs against S.aureus, E. coli, and C. albicans were >50 μM, suggesting TBA-354 is a narrow-spectrum agent. In Caco-2 cell bidirectional permeability assay, TBA-354 showed high permeability at 1 and 10 μM. TBA-354 was metabolically stable or moderately metabolized in incubations with liver microsomes. In HLM, TBA-354 (30 μM) showed weak inhibition of CYP3A4-catalyzed testosterone 6-hydroxylation by 40% [1]. In a low-dose aerosol infection model, TBA-354 dosed with 100 mg/kg daily for 5 of 7 days per week for 3 weeks showed significant bactericidal activity and reduced lung CFU by approximately 1 log10. In chronic murine TB, TBA-354 killed M. tuberculosis in a dose- and time-dependent way, and exhibited significant bactericidal activity. TBA-354 has high bioavailability and a long elimination half-life [1]. In murine models of tuberculosis, TBA-354 significantly increased the sterilizing activity of bedaquiline [2].

[1]. Upton AM, Cho S, Yang TJ, et al. In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2015, 59(1): 136-144.
[2]. Tasneen R, Williams K, Amoabeng O, et al. Contribution of the nitroimidazoles PA-824 and TBA-354 to the activity of novel regimens in murine models of tuberculosis. Antimicrob Agents Chemother, 59 :129-135.