The next-generation diarylquinoline TBAJ-587 has superior efficacy against, and restricts selection of, bedaquiline-resistant Rv0678 mutants in a mouse model of tuberculosis
The next-generation diarylquinoline TBAJ-587 has superior efficacy against, and restricts selection of, bedaquiline-resistant Rv0678 mutants in a mouse model of tuberculosis
Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Pre-clinical and clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8x MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 is a clinical candidate with greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that TBAJ-587 has greater efficacy than BDQ against both wild-type M. tuberculosis H37Rv (Figure 1) and an isogenic Rv0678 mutant (Figure 2), whether alone or in combination with pretomanid (Pa) and either linezolid (L) or moxifloxacin (M) and pyrazinamide (Z). TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid (to be presented).
Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Pre-clinical and clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8x MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 is a clinical candidate with greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that TBAJ-587 has greater efficacy than BDQ against both wild-type M. tuberculosis H37Rv (Figure 1) and an isogenic Rv0678 mutant (Figure 2), whether alone or in combination with pretomanid (Pa) and either linezolid (L) or moxifloxacin (M) and pyrazinamide (Z). TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid (to be presented).
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Speaker
Paul J. Converse, PhD
Johns Hopkins University
