期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 65, 期 12, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01412-21
关键词
Mycobacterium tuberculosis; TBAJ-876; bedaquiline; linezolid; mouse; pretomanid; resistance; tuberculosis
资金
- Australia Aid
- Bill and Melinda Gates Foundation
- Germany Federal Ministry of Education and Research through KfW
- Global Health Innovative Technology Fund
- Irish Aid
- Netherlands Ministry of Foreign Affairs
- UK Aid
- TB Alliance
TBAJ-876, a potential new drug, has shown to be more effective than BDQ with a lower MIC against TB strains and higher efficacy in a murine model. Replacing BDQ with TBAJ-876 may lead to shorter treatment duration for TB and more effective treatment against infections caused by Rv0678 mutants.
Bedaquiline (BDQ, B) is the first-in-class diarylquinoline to be approved for treatment of tuberculosis (TB). Recent guidelines recommend its use in treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). The newly approved regimen combining BDQ with pretomanid and linezolid is the first 6-month oral regimen proven to be effective against MDR/XDR-TB. However, the emergence of BDQ resistance, primarily due to inactivating mutations in the Rv0678 gene encoding a repressor of the MmpS5-MmpL5 transporter, threatens to undermine the efficacy of new BDQ-containing regimens. Since the shift in MIC due to these mutations is relatively small (2-8x), safer, and more potent, diarylquinoline analogues may be more effective than BDQ. TBAJ-876, which is in phase 1 trials, has more potent in vitro activity and a superior pre-clinical safety profile than BDQ. Using a murine model of TB, we evaluated the dose-dependent activity of TBAJ-876 compared to BDQ against the wildtype H37Rv strain and an isogenic Rv0678 loss-of-function mutant. Although the mutation affected the MIC of both drugs, the MIC of TBAJ-876 against the mutant was 10fold lower than that of BDQ. TBAJ-876 at doses >= 6.25 mg/kg had greater efficacy against both strains compared to BDQ at 25 mg/kg, when administered alone or in combination with pretomanid and linezolid. Likewise, no selective amplification of BDQ-resistant bacteria was observed at TBAJ-876 doses >= 6.25 mg/kg. These results indicate that replacing BDQ with TBAJ-876 may shorten the duration of TB treatment and be more effective in treating and preventing infections caused by Rv0678 mutants.
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