Identifying potent inhibitors for Mycobacterium tuberculosis MabA (FabG1).

The surge in drug-resistant Mycobacterium tuberculosis (Mtb) strains poses formidable challenges for tuberculosis treatment, emphasizing the pressing need to explore novel therapeutic agents. Mycolic acids, essential for bacterial cell wall formation, are synthesized by two fatty acid synthase (FAS) systems: FAS-I and FAS-II. MabA, an enzyme in the FAS-II system, is vital in the second step of fatty acid biosynthesis and is responsible for the elongation of mycolic acids. In this study, we screened 1,792,771 compounds from seven different databases to screen prospective inhibitors of MabA, an emerging therapeutic target for Mtb. Using a combination of molecular docking, all-atom molecular dynamics simulations, and binding free energy calculations, we identified 48 novel lead compounds from five distinct classes that exhibit significant binding activity against MabA. Of these, 47 compounds demonstrated significantly higher MM/PBSA binding free energy than the only reported MabA inhibitor, compound 29. Altogether, our findings mark a significant advancement towards the rational design of novel therapeutics aimed at combating mycobacterial infections and overcoming drug resistance.