Human Urinary Composition Controls Antibacterial Activity of Siderocalin

Background: During urinary tract infections, humans secrete the protein siderocalin to block bacterial iron uptake. Results: Human urinary pH and metabolite composition strongly affect siderocalin's antibacterial activity. Conclusion: Siderocalin uses a subset of urinary metabolites as cofactors to withhold iron from E. coli in competition with the bacterial siderophore enterobactin. Significance: Therapeutic control of urinary composition may facilitate an important innate antibacterial defense. During Escherichia coli urinary tract infections, cells in the human urinary tract release the antimicrobial protein siderocalin (SCN; also known as lipocalin 2, neutrophil gelatinase-associated lipocalin/NGAL, or 24p3). SCN can interfere with E. coli iron acquisition by sequestering ferric iron complexes with enterobactin, the conserved E. coli siderophore. Here, we find that human urinary constituents can reverse this relationship, instead making enterobactin critical for overcoming SCN-mediated growth restriction. Urinary control of SCN activity exhibits wide ranging individual differences. We used these differences to identify elevated urinary pH and aryl metabolites as key biochemical host factors controlling urinary SCN activity. These aryl metabolites are well known products of intestinal microbial metabolism. Together, these results identify an innate antibacterial immune interaction that is critically dependent upon individualistic chemical features of human urine.