UPEC Transition Metal Control in Virulence: Siderophores, Metallophores, and Clinical Implications Original paper

What was reviewed?

This review synthesizes current evidence on uropathogenic Escherichia coli (UPEC) transition metal control in urinary tract infection, integrating host nutritional immunity, bacterial acquisition of iron, copper, zinc, manganese, and nickel, and the noncanonical functions of siderophores and metallophores in virulence. The diagram on page 5 (Figure 1) maps three import strategies for free ions, host complexes, and siderophore complexes, anchoring a mechanistic framework for pathogenesis. The structural plate on page 7 (Figure 2) compares enterobactin, salmochelin, aerobactin, and yersiniabactin, while the schematic on page 10 (Figure 3) introduces “nutritional passivation,” where yersiniabactin both buffers copper toxicity and preserves copper nutrition.

Who was reviewed?

The authors collate data from human UTI cohorts, transcriptional profiling of voided clinical isolates, murine cystitis and pyelonephritis models, and comparative genomics of uropathogenic Escherichia coli (UPEC). UPEC’s mastery of transition metal control is vital for its adaptability. Evidence includes direct mass spectrometric detection of siderophores in patient urine, expression of metal transport and siderophore genes during human infection, and fitness effects of targeted mutants in vivo. The scope extends to host proteins relevant to nutritional immunity, including lactoferrin, siderocalin, and calprotectin, which shape metal availability in urinary microenvironments.

Most important findings

Metal sequestration by the host is multifaceted. Lactoferrin in neutrophil-rich urine binds iron tightly, calprotectin chelates zinc, manganese, and even ferrous iron and nickel in calcium-rich milieus, and siderocalin limits ferric iron by binding ferric–catechol complexes. Notably, siderocalin’s behavior in urine depends on pH and urinary catechols, which can render iron accessible again to bacterial siderophores. These dynamics position the urinary metabolome as a determinant of UPEC fitness.

UPEC deploys overlapping uptake systems for free Fe(II), Mn(II), Zn(II), and Ni(II) and imports host complexes such as heme and ferric citrate. Virulence links include Sit and MntH for Mn(II)/Fe(II), ZnuABC for zinc, Nik for nickel, ChuA and Hma for heme, and Fec for ferric citrate. These transporters are transcriptionally induced during infection and contribute to bladder or kidney colonization, showcasing the importance of UPEC’s control over transition metals.

Four siderophore systems form a central virulence axis with condition-specific advantages. Enterobactin exhibits ultrahigh Fe(III) affinity and can liberate iron from siderocalin–catechol complexes in urine. Salmochelin, an enterobactin derivative with C-glucosylation, escapes siderocalin binding and supports biofilm and invasion phenotypes via IroN. Aerobactin, less hydrophobic and resistant to siderocalin, performs well in serum-like conditions and is epidemiologically linked to invasive UTI and antibiotic-resistant lineages. Yersiniabactin is both a siderophore and a metallophore that forms stable complexes with copper, cobalt, and nickel, is imported by FyuA, and can be fully recycled after inner membrane transport by YbtPQ. Direct detection of yersiniabactin and its pathway product escherichelin in patient urine underscores in vivo relevance.

Beyond iron capture, yersiniabactin passivates copper toxicity and, as Cu(II)-Ybt, can functionally supply copper to cuproenzymes, balancing toxicity and nutrition. This dual role, illustrated on page 10, improves survival in phagolysosomes and in copper-rich urine, aligning with upregulation of copper efflux systems during human infection. The pathway also produces escherichelin, which inhibits Pseudomonas pyochelin uptake, suggesting interspecies antagonism that may influence community structure in complicated UTIs. These insights identify Major Microbial Associations for a microbiome signatures database that include siderophore systems and their cognate receptors as consistent, virulence-linked features of UPEC across hosts and niches.

Key implications

Therapeutic opportunities include blocking yersiniabactin import, constraining siderophore function, or modulating urinary copper handling to tip the balance from nutritional passivation toward toxicity. Because siderocalin efficacy is contingent on urinary chemistry, strategies that alter urine pH or catechol pools may shift iron away from UPEC. Probiotic bladder colonization with strains that secrete escherichelin-like inhibitors could suppress pyochelin-dependent competitors. UPEC’s tight transition metal control underscores the need for clinical translation, where virulence factor “communities” that co-segregate with specific siderophore systems support multiplexed targeting rather than single-factor inhibition.

Citation

Robinson AE, Heffernan JR, Henderson JP. The iron hand of uropathogenic Escherichia coli: the role of transition metal control in virulence. Future Microbiol. 2018;13(7):813-829. doi:10.2217/fmb-2017-0295.