Computational identification of putative GyrA and AcrR inhibitors from gut microbiota and natural products targeting multidrug-resistant Salmonella enterica

The emergence of multidrug-resistant (MDR) Salmonella enterica poses a critical threat to global health due to its capacity to evade conventional antibiotic therapies. In this study, we employed an integrated in silico strategy combining network pharmacology, molecular docking, ADMET profiling, and molecular simulations to explore diverse metabolites from gut microbiota and natural products as potential inhibitors. Antibiotic resistance genes were retrieved from the Comprehensive Antibiotic Resistance Database and screened via the Antibiotic Resistance Ontology, followed by essentiality analysis using the Database of Essential Genes. Among the identified targets, GyrA and AcrR emerged as key hub proteins through STRING-based protein-protein interaction analysis and pathway enrichment studies. The three-dimensional structures of AcrR and GyrA were obtained from the Protein Data Bank and Swiss-Model respectively, for structural evaluation. Metabolites were collected from the gutMGene and NPASS databases and subjected to docking analysis. Compounds exhibiting binding affinities below - 6.5 kcal/mol were further evaluated for toxicity and pharmacokinetic properties. Penicillin G and indoxyl sulfate metabolite demonstrated favorable ADMET profiles and stable binding interactions, with molecular simulations supporting the structural stability of the ligand-protein complexes. These findings highlight the biodiversity of microbiota and plant-derived metabolites as promising resources against MDR S. enterica, warranting further experimental validation.