Unravelling the nsSNP mediated mechanism of antibiotic resistance in Salmonella enterica serovar Typhi and identification of potential therapeutic alternatives: A genomics and structural bioinformatics study

Abstract

Problem considered: Typhoid fever caused by Salmonella enterica serovar Typhi (Salmonella Typhi) strains with multi-drug resistance (MDR) has become a significant global threat, as existing therapeutic options are limited. To combat this issue, efficient approaches are required to understand the resistance mechanism and identify potential therapeutic alternatives. Methods: In this study, we employed concerted genomics and structural investigation to analyze single nucleotide polymorphisms (SNPs) in putative drug targets from whole genomes of Salmonella Typhi. The impact of these SNPs on the stability of encoded proteins and their effect on functional domains were analyzed to gain better insights into emerging MDR patterns. Results: From the analysis of 360 putative drug target proteins in 60 whole genomes, we identified both prevalent and new mutations. Despite a relatively high conservation (>98 % identity) of protein targets and their functional domains in the MDR variants, INDEL mutations were found to induce local changes. The mutations were profiled as stabilizing or destabilizing based on their structural impact on the respective proteins. Interestingly, the MDR strains showed a preference for stabilizing mutations that altered local flexibility, thus compromising drug-susceptibility. Conclusion: To mitigate the risks associated with antibiotic stress-induced stabilizing mutations in drug targets, we performed virtual screening to identify over 500 potential phytocompounds. Through the screening process, Nimbolide emerged as a promising alternative anti-Typhoid candidate for future experimental validations due to its favourable pharmacokinetic properties, high target affinity (despite mutations), and greater interactive dynamics stability compared to conventional antibiotics.

Keywords

• Nonsynonymous mutations
• Multidrug resistance
• Protein stability
• Nimbolide