Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy.

The urgent need for safer and innovative antitubercular agents remains a priority for the scientific community. In pursuit of this goal, we designed and evaluated novel 5-phenylfuran-2-carboxylic acid derivatives targeting () salicylate synthase (MbtI), a key enzyme, absent in humans, that plays a crucial role in virulence. Several potent MbtI inhibitors demonstrating significant antitubercular activity and a favorable safety profile were identified. Structure-guided optimization yielded 5-(3-cyano-5-isobutoxyphenyl)furan-2-carboxylic acid (), which exhibited strong MbtI inhibition (IC = 11.2 μM) and a promising antitubercular activity (MIC = 32 μM against BCG). Esters of were effectively loaded into poly(2-methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes (POs) and delivered to intracellular mycobacteria, resulting in reduced viability. This study provides a foundation for the use of POs in the development of future MbtI-targeted therapies for tuberculosis.