Comparative Efficacy of the Novel Diarylquinoline TBAJ-876 and Bedaquiline against a Resistant Rv0678 Mutant in a Mouse Model of Tuberculosis.

Abstract

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 (2-8×), 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 wild-type 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 10-fold 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.

• Authors: Deepak Almeida, Paul J Converse, Si-Yang Li, Anna M Upton, Nader Fotouhi, Eric L Nuermberger
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 65 Issue 12 Pg. e0141221 (11 17 2021) ISSN: 1098-6596 [Electronic] United States
• PMID: 34570644 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Diarylquinolines
• TBAJ-876
• bedaquiline

Topics

• Animals
• Antitubercular Agents (pharmacology, therapeutic use)
• Diarylquinolines
• Disease Models, Animal
• Extensively Drug-Resistant Tuberculosis (drug therapy)
• Mice
• Mycobacterium tuberculosis (genetics)
• Tuberculosis, Multidrug-Resistant (drug therapy)