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

Abstract

Lung disease caused by <i>Mycobacterium abscessus</i> 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 <i>in vitro</i> antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 is active against <i>M. abscessus</i> TBAJ-876 displayed submicromolar <i>in vitro</i> activity against reference strains representing the three subspecies of <i>M. abscessus</i> and against a collection of clinical isolates. Drug-drug potency interaction studies with commonly used anti-<i>M. abscessus</i> antibiotics showed no antagonistic effects, suggesting that TBAJ-876 could be coadministered with currently used drugs. Efficacy studies, employing a mouse model of <i>M. abscessus</i> infection, demonstrated potent activity <i>in vivo</i> In summary, we demonstrate that TBAJ-876 shows attractive <i>in vitro</i> and <i>in vivo</i> activities against <i>M. abscessus</i>, similar to its BDQ parent. This suggests that next-generation BDQ, with improved tolerability and pharmacological profiles, may be useful for the treatment of <i>M. abscessus</i> lung disease in addition to the treatment of tuberculosis.