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Xu, Jian; Converse, Paul J; Upton, Anna M; Mdluli, Khisimuzi; Fotouhi, Nader; Nuermberger, Eric L
Antimicrobial agents and chemotherapy, 03/2021, Letnik: 65, Številka: 4Journal Article
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. Clinical reports of emerging BDQ resistance have identified mutations in that derepress 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 to 8× 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 has greater potency than BDQ, including against 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 against wild-type H37Rv and an isogenic mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid.
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in: SICRIS
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