Pan-genome analysis and drug repurposing strategies for extensively drug-resistant Salmonella Typhi: Subtractive genomics and e-pharmacophore approaches.

In the current study, we presented the genome sequence and taxonomic classification of the new extensively drug-resistant (XDR) Salmonella enterica serovar Typhi strain JRCGR-ST-AK02. Its genome size was found to be 4,780,534 bp, containing 4864 genes. Taxonomic classification was performed based on the Average Nucleotide Identity (ANI), Genome-to-Genome Distance Calculator (GGDC) and Average Amino Acid Identity (AAI) analysis. Pan-genome analysis revealed 34,4915 core genes, which are predominantly involved in general functions and carbohydrate metabolism. We used a subtractive genomics approach and identified the PocR protein as a drug target. Its 3D structure was built using homology modeling, and an e-pharmacophore hypothesis was created using its binding site. The pharmacophore hypothesis was screened against FDA-approved ligands library and a total of 2018 out 9392 drugs were selected for molecular docking. Cangrelor and Pentagastrin presented docking scores of -9.503 and -9.081 kcal/mol, respectively. The binding dynamics of these promising FDA-approved drugs were further confirmed through 200 ns molecular dynamics simulation, highlighting their stable and strong interactions with the PocR protein. Our study highlights the potential of Cangrelor and Pentagastrin for repurposing against XDR Salmonella Typhi. By identifying these drugs as promising candidates, we pave the way for new treatments for XDR Salmonella Typhi infections.