Sudapyridine (WX-081) inhibits Mycobacterium tuberculosis by targeting ATP synthase and upregulating host innate immunity.

Drug-resistant tuberculosis (DR-TB) urgently requires safer, more accessible alternatives to bedaquiline (BDQ), which faces critical flaws like cardiotoxicity, high costs, and emerging resistance. WX-081, a promising BDQ alternative, has demonstrated superior anti-TB activity and improved safety in clinical studies. However, its mechanism of action remains unexplored, underscoring the need for further research to optimize its potential in advancing global TB elimination efforts. This study reveals WX-081's dual mechanisms: targeting atpE to disrupt ATP synthase and proton motive force via resistance screening, gene sequencing, and functional assays while enhancing host immunity through macrophage transcriptomics. Molecular docking confirmed atpE binding sites, and immune activation pathways (NF-κB/MAPK) were identified, positioning WX-081 as a potent, safe anti-DR-TB candidate despite unresolved mechanistic details.IMPORTANCEBedaquiline, a key drug for drug-resistant tuberculosis, is restricted by safety issues impacting its clinical utility. Its next-generation alternative, WX-081, has advanced to Phase III trials but lacks in-depth studies on its mechanism and host immune-modulatory effects, necessitating further research before broad clinical adoption.