Computational Evaluation of Fusarium nygamai Compounds as AcrD Efflux Pump Protein Inhibitors of Salmonella Typhimurium.

Abstract

In Salmonella Typhimurium, efflux pump proteins, such as AcrD actively expel drugs and hazardous chemicals from bacterial cells, resulting in treatment failure and the emergence of antibiotic-resistant variants. Focusing on AcrD may lead to the development of novel antimicrobials against multidrug-resistant bacteria. However, challenges persist in achieving high selectivity, low toxicity, and effective bacterial penetration. Natural products, particularly microbial secondary metabolites, possess distinct chemical structures that may target the efflux pump systems. The efflux pump inhibitor capabilities of Fusarium nygamai compounds in Salmonella have not been previously investigated. This study employed molecular docking and molecular dynamics simulations to evaluate 25 F. nygamai compounds as potential inhibitors of AcrD. Additionally, the pharmacological characteristics of these substances were examined. Molecular docking results revealed that 3,6-Dimethoxy-2,5-dinitrobenzonitrile, methyl (2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate, and 7-Methyl-5-nitro-1,4-dihydro-quinoxaline-2,3-dione exhibited the highest binding energies with AcrD. Furthermore, molecular dynamics simulations indicated stable ligand-receptor complex variations over time. This study contributes to the efforts against antibiotic resistance and the improvement of Salmonella infection treatment outcomes globally by facilitating the development of novel therapeutic approaches and enhancing antibiotic efficacy.