A novel SaeS-targeting antivirulence antagonist screened against methicillin-resistant Staphylococcus aureus

The SaeRS two-component system is a major virulence regulator in Staphylococcus aureus, and its sensor kinase SaeS represents a potential target for small-molecule intervention.

In this study, we constructed a library of 1,093 compounds from PubChem and carried out structure-guided virtual screening against the SaeS kinase domain. This approach identified an amide-based candidate, designated Saeamid-1. Molecular docking and molecular dynamics simulations supported stable binding of Saeamid-1 within the nucleotide-binding region of SaeS, with a docking score of -9.884 kcal/mol.

The compound had only limited effects on bacterial growth. In contrast, it reduced hemolytic activity and biofilm biomass in USA300 by 65.74% and 88.77%, respectively. RT-qPCR analysis showed that Saeamid-1 reduced the expression of saeR, saeS, and the SaeRS-associated virulence gene spa.

Taken together, these findings identify Saeamid-1 as a promising antivirulence candidate that targets SaeS in methicillin-resistant Staphylococcus aureus and provide a basis for further development of therapeutic strategies directed against the SaeRS pathway.