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Two-component EvgS protein subdues both antimicrobial resistance and virulence in Shigella flexneri 2a str. 301
  • Aniket Naha,
  • Sudha Ramaiah
Aniket Naha
VIT University
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Sudha Ramaiah
VIT University

Corresponding Author:[email protected]

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Abstract

Shigella flexneri 2a is one of the leading bacterial agents of diarrhoeal mortality in humans. Recently, multi-drug resistance strains have posed severe challenges. The present study was conducted to identify potential drug-target using gene interaction network (GIN) approach in order to understand the molecular mechanisms of both antimicrobial resistance (AMR) and virulence posed by the bacteria. Differential gene expression (DGE) and structural analysis were incorporated to validate our findings. Functional enrichments and topological matrices revealed evgS, ybjZ, tolC, gyrA, parC and their direct interactors to be associated with diverse AMR mechanisms. Since the druggability of TolC, GyrA, and ParC has already been exploited, the current study explored EvgS as a potential alternate drug-target candidate due to its highest prevalence in both GINs interconnecting several genes of two component system (TCS). DGE patterns in ΔPhoPQ (deleted regulatory PhoP and sensor PhoQ) led to the upregulation of TCS comprising EvgSA thereby validating EvgS as a promising therapeutic biomarker. Druggability and structural stability of EvgS was assessed through thermal shifts, backbone stability and coarse dynamics refinement. Structure-function relationship was established revealing the C-terminal extracellular domain as the drug binding site which was further validated through molecular dynamics simulation. Our findings would be pivotal for experimental biologists in designing effective lead molecules against EvgS for establishing successful therapeutic remedies against shigellosis.