Combining molecular modelling and experimental approaches to gain mechanistic insights into the LuxP drug target in Streptococcus pyogens.

Autoinducer-2 can mediate inter- and intra-species communication signal between bacteria and these signals from AI-2 is noted from limited species of bacteria. In humans, S. pyogenes is a pathogen that causes a wide range of illnesses and can survive in the host system and transmit infection. The process by which S. pyogenes acquires the competence to live and disseminate infection remains unknown. We hypothesized that AI-2 and their receptors would play a significant role during infection, and for that present investigation provides the experimental and molecular insights. In the absence of details about the receptor LuxP and LuxQ, the screening approach provides supporting insights. The evolutionary relationship and similarities of the PBP domain (Spy 1535) and the signal transmission PDZ domain (Spy 1536) were studied in relation to their counterparts in other bacteria. Molecular docking and modeling confirmed the domain-enhanced specificity for AI-2 binding. In vitro studies showed that AI-2, which is present in the cell-free supernatant of S. pyogenes, regulates luminescence in P. luminous and biofilm development in E. coli using the LuxS reporter genes. Examination of S. pyogenes gene expression revealed modulation of virulence genes when the pathogen was exposed to V. harveyi HSL and AI-2. Therefore, S. pyogenes pathogenicity is sequentially regulated by AI-2 it acquires from other commensal bacteria. Overall, this study lays the groundwork for understanding the signalling mechanism from AI-2, which are critical to the pathogenic mechanism of S. pyogenes.Communicated by Ramaswamy H. Sarma.