A proteo-genomic comparative analysis reveals an exceptional secretory system type 4 as determinant of evolution resistance in extensively drug resistant H58 Salmonella typhi.

Abstract

Background: Salmonella enterica subsp. enterica serotype Typhi (S. typhi) is the causative agent of human typhoid fever. Although antibiotics have significantly reduced the mortality associated with typhoid, the emergence of Extensively Drug Resistant (XDR) strains, such as the H58 strain, presents a serious challenge to effective treatment. This highlights the urgent need for new therapeutic targets to combat S. typhi infections, especially in the context of increasing drug resistance.

Methods: This study aimed to conduct a comprehensive genomic analysis of the XDR H58 strain by comparing its genome with those of Multi-Drug Resistant (MDR) strains (Global (CT-18) and Asian (343,077_213,147)) and Non-Resistant (NR) strains (Global (Ty2) and Asian (STyphi_1553)). Genomic data were retrieved from NCBI, and comparative analyses were performed to identify strain-specific gene clusters, novel proteins, and unique resistance features. Subtractive genomics was applied to prioritize potential drug targets from the novel proteins identified, focusing on those with essential functions unique to the XDR strain. Phylogenetic analysis was conducted to trace the evolutionary relationships of potential drug targets across different S. typhi strains.

Results: Comparative genomic analysis revealed two gene clusters-Thiopeptide and Non-Ribosomal Peptide Synthetases (NRPS)-in the XDR H58 strain, similar to those in other Asian S. typhi strains (343,077_213,147 and STyphi_1553), suggesting shared resistance mechanisms. Approximately 240 novel proteins were uniquely expressed in the XDR strain. Subtractive genomics highlighted the distinctive presence of the Type 4 Secretion System (T4SS), setting the XDR strain apart from others. Notably, the VirB11 protein, a subunit of the T4SS, was identified as a promising drug target. Phylogenetic analysis of VirB11 across multiple species showed its strong association with MDR strains, further supporting its therapeutic potential.

Conclusions: This study identifies novel proteins and pathways that are uniquely expressed in the XDR H58 strain of S. typhi, with VirB11 protein emerging as a strong candidate for drug development. The findings emphasized the potential of targeting the Type 4 Secretion System to combat the spread of XDR strains. Further experimental validation is needed to confirm the suitability of these targets for therapeutic applications. Ultimately, these insights may contribute to advancing the drug discovery pipeline against the escalating threat of S. typhi infections.