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

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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6591646 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Zhang Ye Y Zhu Hui H Fu Lei L Wang Bin B Guo Shaochen S Chen Xi X Liu Zhongquan Z Huang Haihong H Yang Tianjian T Lu Yu Y

Antimicrobial agents and chemotherapy 20190624 7

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), ...[more]

PMID: 31061157

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Project description:Mycobacterium tuberculosis (Mtb) represents one of the most persistent bacterial threats to human health and new drugs are needed to limit its impact. Conditional knockdown mutants can help validate new drug targets, but the analysis of individual mutants is laborious and time consuming. Here, we describe quantitative DNA tags (qTags) and their use to simultaneously analyze conditional Mtb knockdown mutants that allowed silencing the glyoxylate and methylcitrate cycles (via depletion of isocitrate lyase, ICL), the serine protease Rv3671c, and the core subunits of the mycobacterial proteasome, PrcB and PrcA. The impact of gene silencing in multi-strain cultures was determined by measuring the relative abundance of mutant-specific qTags with real-time PCR. This achieved accurate quantification over a broad range of qTag abundances and depletion of ICL, Rv3671c, or PrcBA resulted in the expected impairment of growth of Mtb with butyrate as the primary carbon source, survival during oxidative stress, acid stress and starvation. The impact of depleting ICL, Rv3671c, or PrcBA in multi-strain mouse infections was analyzed with two approaches. We first measured the relative abundance of mutant-specific qTags in total chromosomal DNA isolated from bacteria that were recovered from infected lungs on agar plates. We then developed a two-step amplification procedure, which allowed us to measure the abundances of individual mutants directly in infected lung tissue. Both strategies confirmed that inactivation of Rv3671c and PrcBA severely reduced persistence of Mtb in mice. The multi-strain infections furthermore suggested that silencing ICL not only prevented growth of Mtb during acute infections but also prevented survival of Mtb during chronic infections. Analyses of the ICL knockdown mutant in single-strain infections confirmed this and demonstrated that silencing of ICL during chronic infections impaired persistence of Mtb to the extent that the pathogen was cleared from the lungs of most mice.

Dataset Information

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

Publications

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

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