The Extracellular Metallometabolome: Metallophores, Metal Ionophores, and Other Chelating Agents as Natural Products Original paper

What was reviewed?

This review introduces the extracellular metallometabolome, the suite of secreted metallophores, metal ionophores, and other chelators that shape metal availability outside cells and drive outcomes at the host–microbe interface. It explains how microbes and hosts use these small molecules to acquire needed metals, withhold them from rivals, or intoxicate invaders, and shows how this chemistry steers colonization, inflammation, and virulence across human niches relevant to the microbiome.

Who was reviewed?

The article surveys bacteria, fungi, and plants that secrete metal-binding natural products and the human host proteins that counter them. It details chalkophores such as methanobactins, broad-spectrum opine metallophores like staphylopine in Staphylococcus aureus and pseudopaline in Pseudomonas aeruginosa, and siderophores that moonlight as zincophores or chalkophores, including yersiniabactin used by uropathogenic Escherichia coli. It also covers fungal zincophores (Pra1 from Candida albicans and Aspf2 from Aspergillus fumigatus) and host defenses such as lipocalin-2 interception of siderophores and calprotectin sequestration of zinc and manganese. The review emphasizes how local pH and inflamed mucosa tune metal speciation and ligand selectivity in the gut, urinary tract, and airway.

Most important findings

The review shows that secreted metal ligands act as precise ecological tools that feed, starve, or poison microbes, and that many “siderophores” function as general metallophores whose metal choice depends on niche chemistry. Yersiniabactin illustrates this plasticity: it binds copper and zinc in addition to iron, helps Enterobacterales withstand copper stress in the urinary tract, and supports colonization in the inflamed gut where calprotectin restricts zinc. Staphylopine helps S. aureus overcome zinc starvation imposed by calprotectin, yet because it can also carry copper, it can turn into a liability under copper stress. Methanobactins exemplify high-affinity chalkophores that reduce Cu(II) to Cu(I) and deliver it for enzyme function, while frankobactins show that some “siderophores” primarily detoxify copper rather than acquire iron. The host counters with nutritional immunity, raising copper and withholding iron and zinc; lipocalin-2 traps classic siderophores, while stealth forms such as salmochelins evade it.

Across niches, pH shifts alter metal selectivity of ligands and thus rewire uptake hierarchies, explaining why the same metallophore can favor different metals in the stomach, small bowel, or bladder. For a microbiome signatures database, the paper highlights actionable markers: presence of yersiniabactin or salmochelin loci in Enterobacterales, staphylopine/pseudopaline operons in S. aureus/P. aeruginosa, fungal zincophore genes (PRA1/ASPF2), and host factors such as calprotectin or lipocalin-2 that gate metal flows and remodel community structure.

Key implications

Clinicians can use metallophore and ionophore biology to interpret and influence dysbiosis and infection risk. Genomic detection of yersiniabactin or staphylopine modules suggests metal-adaptive traits that support persistence under inflammation and predict niche preference, while elevated calprotectin or alkaline pH signals a shift toward zinc scarcity and altered ligand selectivity. Careful copper or zinc modulation, topical or systemic, may tilt control toward the host but must avoid collateral mucosal injury. Therapeutic ideas include ligand-decoy strategies that block uptake, lipocalin-2–sensitizing approaches for non-stealth siderophores, and timed metal modulation that exploits broad-spectrum metallophores’ liabilities during copper stress. Embedding these loci and host biomarkers in microbiome reports can refine risk stratification for recurrent UTI, candidiasis, and airway infections and guide metal-aware stewardship.