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 Mycobacterium tuberculosis (Mtb) salicylate synthase (MbtI), a key enzyme, absent in
humans, that plays a crucial role in Mtb 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 (1e), which exhibited strong MbtI inhibition (IC50 = 11.2 μM) and a promising in vitro antitubercular activity (MIC99 = 32 μM against M. bovis BCG). Esters of 1e 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 Mtb viability. This study provides a foundation for the use of POs in
the development of future MbtI-targeted therapies for tuberculosis.