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Antimicrob Agents Chemother. 2019 Jun 24;63(7). pii: e02496-18. doi: 10.1128/AAC.02496-18. Print 2019 Jul.

Identifying Regimens Containing TBI-166, a New Drug Candidate against Mycobacterium tuberculosis In Vitro and In Vivo.

Author information

1
Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China.
2
Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
3
Global Alliance for TB Drug Development, New York, New York, USA.
4
Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China luyu4876@hotmail.com.
#
Contributed equally

Abstract

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-166+BDQ, TBI-166+PZA, TBI-166+BDQ+LZD, TBI-166+BDQ+PMD, and TBI-166+BDQ+PMD+LZD-showed significantly more potent efficacy after 4 weeks of treatment compared to the control regimen, INH+RFP+PZA. 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-166+BDQ+LZD > TBI-166+BDQ > TBI-166+PZA > TBI-166+BDQ+PMD+LZD > TBI-166+BDQ+PMD. In C3HeB/FeJNju mice, TBI-166+BDQ+LZD 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-166+BDQ+LZD regimen is recommended for further testing in a TBI-166 phase IIb clinical trial.

KEYWORDS:

BALB/c mice; C3HeB/FeJNju mice; TBI-166; murine model; tuberculosis

PMID:
31061157
PMCID:
PMC6591646
[Available on 2019-12-24]
DOI:
10.1128/AAC.02496-18

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