Non-classical roles of bacterial siderophores in pathogenesis. Original paper

What was reviewed?

This mini-review explains the non-classical roles of bacterial siderophores beyond iron capture and shows how these small molecules shape pathogenesis by handling other metals, buffering oxidative stress, and sending signals that tune virulence. The author outlines how siderophores bind copper, zinc, and nickel, block copper redox cycling, and even act as delivery systems for non-iron metals. The paper also covers siderophore-driven signaling that boosts virulence factor output, and class IIb microcins that hijack siderophore receptors to kill rivals. These insights link metal chemistry to real infection sites and give direct markers that clinicians can track in microbiome profiles.

Who was reviewed?

The review surveys key pathogens and niches that matter in clinical care and highlights uropathogenic Escherichia coli that use yersiniabactin to bind copper in urine and to gain zinc when calprotectin lowers zinc during cystitis or gut inflammation. It details Pseudomonas aeruginosa pyoverdine and pyochelin, which change with copper exposure and reactive oxygen stress and drive signaling that raises toxins. It includes Yersinia pestis where yersiniabactin can back up zinc uptake and support flea and mammalian infection, and touches probiotic E. coli Nissle that uses yersiniabactin to colonize the inflamed, zinc-poor gut. Host factors appear throughout, such as neutrophil and macrophage metal pressure, calprotectin that withholds zinc, and ATP7A that routes copper into phagosomes.

Most important findings

The core message is that siderophores act as broad metallophores and signals that shift survival under host metal stress. Yersiniabactin binds Cu(II) and prevents its reduction to more toxic Cu(I), which protects Enterobacterales in copper-rich urine; the same system can import Cu(II) and Ni(II) for enzyme use, and can favor zinc uptake when calprotectin lowers zinc in inflamed tissue. Catecholate siderophores such as enterobactin can worsen copper injury by driving Cu(II) to Cu(I), but E. coli CueO oxidase can blunt this effect, showing a clear circuit that predicts copper tolerance when cueO is present. In P. aeruginosa, copper raises pyoverdine genes, pyoverdine and pyochelin mediate stepwise signaling that boosts virulence factors, and oxidative stress triggers “privatization” of pyoverdine to resist damage. Yersiniabactin also behaves as an autoinducer: the Cu(II)–yersiniabactin complex activates the YbtA regulator and increases yersiniabactin and receptor expression, which links copper levels to siderophore supply and uptake.

Key implications

Clinicians can use siderophore modules as clear signatures of metal-adapted pathogens. Finding yersiniabactin in urinary isolates predicts copper-tolerant Enterobacterales and helps explain recurrent cystitis under copper stress. In an inflamed bowel, yersiniabactin with high calprotectin predicts zinc-savvy Enterobacterales that outcompete commensals. Detecting pyoverdine and pyochelin circuits in airway samples points to signaling-driven virulence and stress control in Pseudomonas. These signals also warn that copper-based devices or supplements may select for yersiniabactin-positive strains, while iron chelators can provoke inflammation or shift metal balance. Therapeutic ideas include blocking siderophore biosynthesis or uptake, using decoys that soak up metallophores, and pairing standard therapy with metal-aware steps that avoid feeding the very traits that promote persistence. Reporting siderophore loci with host markers like calprotectin or ATP7A in microbiome results can improve risk calls and guide targeted care.