TBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessus

Lung disease caused by Mycobacterium abscessus is very difficult to cure, and treatment failure rates are high. The antituberculosis drug bedaquiline (BDQ) is used as salvage therapy against this dreadful disease. However, BDQ is highly lipophilic, displays a long terminal half-life, and presents a cardiotoxicity liability associated with QT interval prolongation. Recent medicinal chemistry campaigns resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ which are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, a clinical development candidate of this series, shows attractive in vitro antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ876 is active against M. abscessus. TBAJ-876 displayed submicromolar in vitro activity against reference strains representing the three subspecies of M. abscessus and against a collection of clinical isolates. Drug-drug potency interaction studies with commonly used anti-M. abscessus antibiotics showed no antagonistic effects, suggesting that TBAJ-876 could be coadministered with currently used drugs. Efficacy studies, employing a mouse model of M. abscessus infection, demonstrated potent activity in vivo. In summary, we demonstrate that TBAJ-876 shows attractive in vitro and in vivo activities against M. abscessus, similar to its BDQ parent. This suggests that next-generation BDQ, with improved tolerability and pharmacological profiles, may be useful for the treatment of M. abscessus lung disease in addition to the treatment of tuberculosis.