In-Silico Identification of Phytochemical Inhibitors of Mycobacterium tuberculosis Efflux Pumps: A Potential Strategy against Multidrug Resistance

Background: Efflux pump-mediated antibiotic extrusion is a key mechanism of multidrug resistance in Mycobacterium tuberculosis (MTB). Inhibiting these pumps is a promising strategy for resensitizing resistant strains to conventional antibiotics.
Materials & Methods: An integrated in silico approach was employed to evaluate the interaction of drug-like ligands, primarily phytochemicals, with key MTB efflux pumps. Homology models of DrrA, DrrB, and DrrC proteins and the crystal structure of Rv1819c were used for molecular docking. Top-scoring ligands were subsequently analyzed for drug-likeness, toxicity profile, and binding stability via molecular dynamics (MD) simulations to identify the most promising efflux pump inhibitors (EPIs).
Findings: Molecular docking revealed high-affinity binding of several phytochemicals. The top-scoring ligands were curcumin, rosmarinic acid, and pracinostat for DrrA; curcumin, kanzonol C, and Skf-100330A for DrrB; and rosmarinic acid, curcumin, and kanzonol C for DrrC. For the Rv1819c protein, the top-scoring compounds were crocetin, curcumin, and kanzonol C, which were found to bind specifically to the ATP-interacting pocket. An integrated analysis of docking affinity, molecular dynamics stability, toxicity, and drug-likeness identified curcumin, kanzonol C, rosmarinic acid, and crocetin as the most promising candidate EPIs.
Conclusion: The present in-silico study identified curcumin, kanzonol C, rosmarinic acid, and crocetin as promising phytochemical inhibitors of key MTB efflux pumps. These compounds exhibited potential for synergistic activity with conventional anti-tuberculosis drugs. Therefore, preclinical and experimental validation is warranted to confirm their efficacy as efflux pump inhibitors.