Computational and Experimental Characterization of Mycobacterium marinum β-Carbonic Anhydrase Inhibitors

Abstract

Carbonic anhydrases in Mycobacterium tuberculosis are increasingly recognized as promising therapeutic targets in drug-resistant tuberculosis. In this study, a homology model of β-carbonic anhydrase was developed using the closely related Mycobacterium marinum sequence as a structural basis. A focused antituberculosis compound library was screened, identifying 2 ligands, F2686-0257 and F1011-1367, with strong binding affinities and distinct interaction patterns. Molecular dynamics simulations more than 100 ns confirmed stable backbones and conserved binding pockets, with F2686-0257 stabilized by aromatic anchoring and F1011-1367 by polar interactions. Structure-activity relationship analysis highlighted rigid aromatic scaffolds, controlled molecular size, and balanced polarity as favorable features. In M marinum growth assays, F2686-0257 inhibited bacterial proliferation at 100 µM and enhanced rifampicin activity, whereas F1011-1367 showed weaker inhibition without synergy. The compounds also showed favorable ADMET and drug-likeliness properties. These results support β-carbonic anhydrase as a viable target and provide scaffolds for the rational development of novel antitubercular agents.