Natural hydroxy-isoflavone
as potential modulator of Salmonella virulence, targeting the T3SS complex at host-pathogen
interface
Varma Aryan, Tripathi Swati, Sahni Deepak, Bharati Akhilendra Pratap and Sharma
Chandresh
Res. J. Biotech.; Vol. 21(1); 249-261;
doi: https://doi.org/10.25303/211rjbt2490261; (2026)
Abstract
Salmonella are acquiring resistance to conventional antibiotics, comprising of fluoroquinolones
providing limited treatment options to enteric fever. Similar to many Gram-negative
bacteria, Salmonella pathogenicity island-1 (SPI-1) encodes Type Three Secretion
System (T3SS), which forms invasosomes. T3SS needle complex at the host-pathogen
interface allows Salmonella invasion proteins (Sips) to stimulate membrane ruffles
and facilitate pathogen uptake through intimate attachment. Therefore, the present
study intends to repurpose naturally derived small molecules against Sips, which
may potentially block SPI-1-mediated virulence and inhibit Salmonella invasion.
Invasosomes-associated target virulence factor (t2785) of S. typhi, was modelled
through the SWISS-MODEL platform. A naturally derived compound library was used
for screening based on their ligand binding affinity, adhering to designated grid
coordinates. Data was analyzed and visualized post screening. Modelling of Sip from
S. typhi revealed a 3D structure homologous to S. typhimurium Sip (PDB: 2YM9).
Screening resulted 7 promising hydroxyisoflavones, interacting with the receptor
pocket, made up of negatively charged amino acids (D147, S148, T219 etc.). Among
the binder hydroxyisoflavones, four demonstrated a stronger affinity towards structural
Sip(s) involved in rearrangement and formation of the T3SS-needle complex. Hence,
repurposed naturally derived small molecules against Sips, may impede T3SS complex
at host-pathogen interface and potentially inhibit Salmonella invasion.
