Harnessing microbial-derived metabolites in the urinary tract to prevent infection induced catheter encrustation

Proteus mirabilis is a predominant cause of catheter associated urinary tract infection (CAUTI), and a key virulence factor is its urease enzyme which hydrolyzes urea to ammonia. This process results in the formation of urinary stones, facilitating catheter blockage and bacteremia. The only FDA approved urease inhibitor, acetohydroxamic acid (AHA), has side effects that limit its clinical use. Common urinary tract colonizers modulate P. mirabilis urease activity via secreted small molecules. A global metabolomics analysis of six modulatory bacterial species revealed 31 candidate urease-dampening metabolites, seven of which were verified to decrease P. mirabilis urease activity. Six metabolites decreased the activity of purified urease enzyme, suggesting a direct mechanism of action, and all seven dampened urease activity in at least two other urease-positive bacterial species. One metabolite (D-imidazole lactate) demonstrated antimicrobial activity and decreased expression of the urease operon in P. mirabilis. All pairwise combinations of metabolites and AHA were assessed for synergistic reduction in P. mirabilis urease activity. Ten combinations demonstrated significant synergistic dampening, and two were further validated to prevent catheter encrustation in an in vitro model for CAUTI. Prophylactic use of urease dampening metabolites with AHA could improve the efficacy of antimicrobial treatment against catheter biofilms.