Pangenome diversification and resistance gene characterization in Salmonella Typhi prioritized RfaJ as a significant therapeutic marker
Background: Salmonella Typhi stands because the etiological agent accountable for the start of human typhoid fever. The pressing interest in innovative therapeutic targets against S. Typhi is underscored through the escalating prevalence of the virus and also the severe nature of their infections. Consequently, this research employs pangenome analysis to scrutinize 119 S. Typhi-resistant strains, planning to find out the most promising therapeutic targets via its core genome.
Results: Subtractive genomics was used to systematically eliminate non-homologous (n=1147), essential (n=551), drug-like (n=80), and pathogenicity-related (n=18) proteins in the initial pool of 3351 core genome proteins. Consequently, lipopolysaccharide 1,2-glucosyltransferase RfaJ was designated because the optimal medicinal target because of its potential versatility. In addition, a compendium of 9000 Food and drug administration-approved compounds was repurposed for evaluation from the RfaJ drug target, using the specific intent of prioritizing novel, high-potency therapeutic candidates for combating S. Typhi. Ultimately, four compounds, namely DB00549 (Zafirlukast), DB15637 (Fluzoparib), DB15688 (Zavegepant), and DB12411 (Bemcentinib), were designated as potential inhibitors in line with the ligand-protein binding affinity (shown by the cheapest anticipated binding energy) and also the overall stability of those compounds. Particularly, molecular dynamics simulations, conducted more than a 50 nanosecond interval, convincingly shown the soundness of those compounds poor the RfaJ protein.
Conclusion: In conclusion, the current findings hold significant promise being an initial stride within the broader drug discovery endeavor against S. Typhi infections. However, the experimental validation from the identified drug target and drug candidate is further needed to improve the potency of the applied methodology.