Tarbiat Modares University Infection Epidemiology and Microbiology 2588-4107 12 1 2026 02 01 In-Silico Identification of Phytochemical Inhibitors of Mycobacterium tuberculosis Efflux Pumps: A Potential Strategy against Multidrug Resistance 37 52 28716 10.66224/iem.12.1.37 EN Seyed Akbar Moosavi Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Iran University of Medical Sciences and Health Services, Tehran, Iran Abdorrahim Absalan Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Iran University of Medical Sciences and Health Services, Tehran, Iran Zahra Absalan Department of Microbiology, Faculty of medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Fereshteh Parto Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Iran University of Medical Sciences and Health Services, Tehran, Iran Journal Article 2025 05 24 <strong>Background:</strong> 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.<br><strong>Materials & Methods:</strong> 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).<br><strong>Findings:</strong> 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.<br><strong>Conclusion: </strong>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. https://iem.modares.ac.ir/article_28716_8ff28835276bec79658f56f14f699674.pdf