؊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 dosedependent 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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TBI-166, derived from riminophenazine analogues, is under development in a phase I clinical trial in China. TBI-166 showed more potent anti-tuberculosis (anti-TB) activity than did clofazimine in in vitro and animal experiments. To identify potent regimens containing TBI-166 in TB chemotherapy, TBI-166 was assessed for pharmacological interactions in vitro and in vivo with several anti-TB drugs, including isoniazid (INH), rifampin (RFP), bedaquiline (BDQ), pretomanid (PMD), linezolid (LZD), and pyrazinamide (PZA). Using an in vitro checkerboard method, we found that TBI-166 did not show antagonism or synergy with the tested drugs. The interaction relationship between TBI-166 and each drug was indifferent. In in vivo experiments, aerosol infection models with BALB/c and C3HeB/FeJNju mice were established, testing drugs were administered either individually or combined in treatments containing TBI-166 and one, two, or three other drugs, and the bactericidal activities were determined after 4-and 8-week therapeutic treatments. In BALB/c mice, five TBI-166-containing regimens-TBI-166ϩBDQ, TBI-166ϩPZA, TBI-166ϩBDQϩLZD, TBI-166ϩBDQϩPMD, and TBI-166ϩBDQϩPMDϩLZD-showed significantly more potent efficacy after 4 weeks of treatment compared to the control regimen, INHϩRFPϩPZA. At the end of an 8-week treatment, lung log CFU counts decreased to undetectable levels in mice treated with each of the five regimens. The rank order of the potency of the five regimens was as follows: TBI-166ϩBDQϩLZD Ͼ TBI-166ϩBDQ Ͼ TBI-166ϩPZA Ͼ TBI-166ϩBDQϩPMDϩLZD Ͼ TBI-166ϩBDQϩPMD. In C3HeB/FeJNju mice, TBI-166ϩ BDQϩLZD was also the most effective of the TBI-166-containing regimens. In conclusion, five potent chemotherapy regimens that included TBI-166 were identified. The TBI-166ϩBDQϩLZD regimen is recommended for further testing in a TBI-166 phase IIb clinical trial.

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