Siderophore-Mediated Iron Acquisition in Gram-Negative Bacteria

The acquisition of iron is vital for bacterial growth and pathogenicity. In Gram-negative bacteria, low concentrations of bioavailable ferric iron (Fe3+) in host and environmental niches have driven the evolution of high-affinity iron-chelating compounds known as siderophores. These small molecules are secreted into the extracellular milieu to scavenge Fe3+, forming a siderophore–iron complex that is subsequently recognised by specific outer-membrane receptors. Uptake is typically mediated through TonB-dependent transporters that transduce energy from the inner membrane to facilitate passage across the outer membrane. Once in the periplasm, periplasmic binding proteins and inner-membrane ATP-binding cassette systems transport the complex into the cytoplasm, where iron is released and reduced for incorporation into cellular cofactors. This multi-step pathway not only secures essential nutrients but also represents a key virulence determinant in many pathogens. Beyond native siderophores such as enterobactin and pyoverdine, bacteria can pirate heterologous siderophores through receptor promiscuity, enhancing survival in competitive environments. The strategic coupling of antibiotics to siderophores—the Trojan Horse approach—has further extended these systems into novel therapeutic modalities, exploiting bacterial iron uptake to deliver antimicrobial agents selectively. The diversity of siderophore structures and transport mechanisms underpins their global significance in microbial ecology, pathogenesis and the development of next-generation antibacterial strategies.

Research from Nature Portfolio

Recent synthetic efforts have realised the total synthesis of albomycins, a class of peptidylnucleoside sideromycins with potent antibacterial activity. These studies validated the natural structures and enabled access to analogues that exhibit selective toxicity against critical pathogens. By reconstructing the biosynthetic architecture, researchers generated albomycin variants that harness hydroxamate-type siderophore transport systems to smuggle antibiotic moieties into the cell. Detailed antimicrobial assays demonstrated efficacy against both Gram-positive and Gram-negative clinical isolates, underscoring the therapeutic promise of siderophore–antibiotic conjugates.

Siderophore-Mediated Iron Acquisition in Gram-Negative Bacteria publication trend

The graph below shows the total number of articles in siderophore-mediated iron acquisition in gram-negative bacteria across all publications each year (not limited to Nature Index journals).

Technical terms

Siderophore: A small, high-affinity iron-chelating molecule secreted by bacteria to acquire ferric iron.

TonB-dependent transporter: An outer-membrane protein that uses energy from the TonB–ExbB–ExbD complex to import siderophore–iron complexes into the periplasm.

Periplasmic binding protein: A soluble protein in the periplasm that shuttles siderophore–iron complexes to inner-membrane transporters.

ATP-binding cassette (ABC) transporter: An inner-membrane protein complex that uses ATP hydrolysis to translocate siderophore–iron complexes into the cytoplasm.

Trojan Horse strategy: The coupling of an antibiotic to a siderophore to exploit bacterial iron uptake pathways for targeted drug delivery.

References

1. SIDERITE: Unveiling hidden siderophore diversity in the chemical space through digital exploration. iMeta (2024).
2. A Novel Natural Siderophore Antibiotic Conjugate Reveals a Chemical Approach to Macromolecule Coupling. ACS Central Science (2023).
3. Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens. Nature Communications (2018).