The siderophore yersiniabactin binds copper to protect pathogens during infection

Bacterial pathogens secrete chemically diverse iron chelators called siderophores, which may exert additional distinctive functions in vivo. Among these, uropathogenic E.coli often co-express the virulence-associated siderophore yersiniabactin (Ybt) along with catecholate siderophores. Here we used a novel mass-spectrometric screening approach to reveal that yersiniabactin is also a physiologically favorable copper (II) ligand. Direct mass-spectrometric detection of the resulting Cu(II)-Ybt complex in mice and humans with E. coli urinary tract infections demonstrates copper binding to be a physiologically relevant in vivo interaction during infection. Yersiniabactin expression corresponded to higher copper resistance among human urinary tract isolates, suggesting a protective role for this interaction. Chemical and genetic characterization showed that yersiniabactin helps bacteria resist copper toxicity by sequestering host-derived copper (II) and preventing its catechol-mediated reduction to copper (I). Together, these studies reveal a new virulence-associated function for yersiniabactin that is distinct from iron binding.