Beyond bedaquiline: the new generation of mycobacterial adenosine triphosphate synthase inhibitors TBAJ-587, TBAJ-876, and WX-081 for the treatment of drug-resistant tuberculosis

Tuberculosis (TB) remains a major global health threat, exacerbated by the emergence of drug-resistant TB (DR-TB). Bedaquiline represents a breakthrough in TB treatment as the first novel drug approved in nearly five decades. However, bedaquiline’s limitations, including safety concerns and high resistance risk, have prompted research into second-generation bedaquiline analogs. This review focuses on the structural modifications, pharmacodynamics, antibacterial mechanisms, ADMET profiles, clinical research, and synthesis strategies of bedaquiline (BDQ) and its analogs. Through structural modifications, compounds like TBAJ-587, TBAJ-876, and WX-081 have maintained potent antitubercular activity while improving pharmacokinetic properties, reducing toxicity, and lowering resistance risk. These novel drugs demonstrate promising efficacy and safety in clinical trials, making them potential alternatives to BDQ for DR-B.