Overexpression of Agr quorum sensing system in uropathogenic Staphylococcus aureus in response to simulated urinary metabolic conditions enhancing growth and virulence.

Staphylococcus aureus (S. aureus) is a major opportunistic pathogen, causing acute and chronic infections including urinary tract infection (UTI). S. aureus relies on the Accessory gene regulator (Agr), a central quorum sensing (QS) system and the urease genes ureABCEFGD, for the regulation of urease expression and its pathogenicity. Urease is a key virulence factor for S. aureus, modulating immune responses by altering the local urinary pH and impairing immune defenses in the hostile urinary environment. QS is regulated by the external stimuli and in urological disease, the role of different urinary metabolite conditions and pH on the urease expression and Agr-QS regulation remains poorly understood. In this study, we explored the growth, biofilm formation, and urease activity under various simulated urinary metabolic and pH environments to study the response of S. aureus strains isolated from patients with urological diseases. The expression levels of QS genes and urease genes were compared in different urinary conditions that included the conditions from which the strains were isolated. A correlation analysis was used to study the associations between growth, pH changes, urease activity, biofilm formation, and the expression of agr and ure genes to predict their regulatory relationships. Our results demonstrated significant differences across glycosuria, haematuria, creatininuria, and albuminuria in growth, biofilm formation, and urease activity in S. aureus strains (p < 0.001). Significantly higher growth and urease activity were noted in glycosuria and haematuria-originated strains under the similar simulated conditions (p < 0.001). However, all the simulated conditions increased the expression levels of agr and ure genes; in the pre-adapted environment, favoring their survival highlighting niche adaptation. The simulated conditions with acidic pH significantly overexpressed the agr and ure genes compared to alkaline pH (p < 0.001). Increased expression profile of the QS system under the disease specific urine metabolic conditions, suggests its role in promoting bacterial fitness in the urinary environment and also forms the basis of managing UTI with targeted approach.