Lung disease caused by is very difficult to cure and treatment failure rates are high. The anti-tuberculosis drug bedaquiline (BDQ) is used as salvage therapy against this dreadful disease. However, BDQ is highly lipophilic, displays long terminal half-life and presents a cardio-toxicity 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 cardio-toxic potential. TBAJ-876, a clinical development candidate of this series, shows attractive anti-tubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 is active against TBAJ-876 displayed sub-μM activity against reference strains representing the three subspecies of and against a collection of clinical isolates. Drug-drug potency interaction studies with commonly used anti- antibiotics showed no antagonistic effects, suggesting that TBAJ-876 could be co-administered with currently used drugs. Efficacy studies, employing a mouse model of infection, demonstrated potent activity In summary, we demonstrate that TBAJ-876 shows attractive and activity against , similar to its BDQ parent. This suggests that next generation BDQ, with improved tolerability and pharmacological profile, may be useful for the treatment of lung disease in addition to the treatment of tuberculosis.
Copyright © 2020 Sarathy et al.