The siderophore yersiniabactin binds copper to protect pathogens during infection Original paper

What was studied?

This original study shows that yersiniabactin binds copper in vivo and protects uropathogenic Escherichia coli during urinary infection. The authors used targeted mass spectrometry to detect the Cu(II)–yersiniabactin complex directly in mouse and human urine, then tested whether this chemistry changes copper stress and survival. They compared the growth and viability of strains that make yersiniabactin with mutants that lack it, probed competition with catecholate siderophores, and measured how apo-yersiniabactin prevents toxic copper redox cycling. By pairing metabolite detection with functional assays, the study links a clear biochemical event to a survival advantage under host copper pressure in the urinary tract, and it reframes a classic “iron siderophore” as a broader metallophore with clinical impact.

Who was studied?

The work focused on uropathogenic E. coli (UPEC), centered on strain UTI89 and isogenic mutants that lack yersiniabactin biosynthesis (ΔybtS) or catecholate production (ΔentB). The team analyzed urine and bladder tissue from infected C3H/HeN mice, and they examined midstream urine from women with acute cystitis, confirming whether the infecting isolate expressed yersiniabactin. In both hosts, liquid chromatography–mass spectrometry detected the Cu(II)–yersiniabactin complex, often in excess of the Fe(III)–yersiniabactin form, which shows that copper binding occurs during infection and not only in vitro. They then linked this signal to phenotype by showing that clinical urinary isolates resist copper more than non-urinary strains from the same patients and that apo-yersiniabactin rescues a biosynthetic mutant from copper toxicity, thereby tying human findings to mechanistic tests.

Most important findings

Yersiniabactin formed a stable complex with Cu(II) in physiologic fluids and did so in vivo during UTI, with most mouse and human samples showing more Cu(II)–yersiniabactin than Fe(III)–yersiniabactin. Yersiniabactin expression correlated with higher copper resistance among urinary isolates, and loss of yersiniabactin sensitized UTI89 to copper; adding apo-yersiniabactin restored survival, but adding pre-formed Cu(II)–yersiniabactin did not, which proves that open copper-binding capacity drives protection. The study also resolved opposing roles for siderophore classes: catecholate siderophores, including enterobactin or its 2,3-dihydroxybenzoate moiety, reduced Cu(II) to more toxic Cu(I) and deepened killing, while yersiniabactin prevented that reduction by sequestering Cu(II) first. Together these data define a clean microbiome signature for UPEC: presence of the yersiniabactin locus predicts copper tolerance in the urinary niche, whereas abundant catecholate output without yersiniabactin predicts copper-sensitized growth.

Key implications

Clinicians can read yersiniabactin as a copper-protection trait that helps UPEC persist during inflammation, when local copper rises. In a microbiome signatures database, tag “yersiniabactin binds copper” with features that include in vivo Cu(II)–yersiniabactin detection, improved survival under micromolar copper, and the protective block of catecholate-driven Cu(II)→Cu(I) reduction. Pair this with genomic markers such as the yersiniabactin receptor gene fyuA and biosynthetic genes to flag strains suited for the urinary tract. These markers explain why yersiniabactin-positive Enterobacterales expand in copper-stressed urine and why copper-based device or topical strategies may select for such strains. Therapeutically, blocking yersiniabactin biosynthesis or uptake could unmask catecholate-dependent copper toxicity and tip control toward the host, while care with exogenous copper exposure can avoid favoring copper-tolerant pathobionts in recurrent UTI.