Bacterial siderophore-mediated iron uptake system

The bacterial siderophore-mediated iron uptake system is a critical survival mechanism used by pathogenic bacteria to acquire essential ferric iron (Fe3+) from the host environment, where free iron is extremely scarce (PubMed: 32103171). Bacteria secrete siderophores—small, high-affinity iron-chelating molecules—that bind iron and are subsequently recognized by specific outer membrane receptors, such as TonB-dependent transporters, for active uptake into the cell (UniProt: P06971). Because iron is indispensable for bacterial growth and virulence, this system serves as a potent therapeutic target (PubMed: 28846531). The most successful clinical application is the Trojan Horse strategy, exemplified by the antibiotic cefiderocol, which uses a siderophore-like moiety to gain entry into multi-drug resistant Gram-negative bacteria (FDA: 212966). By exploiting these active transport pathways, drugs can overcome the low permeability of the bacterial outer membrane, making this system a focal point for developing novel anti-infectives against highly resistant pathogens (PubMed: 31586111). Beyond drug delivery, inhibiting siderophore biosynthesis or the transport machinery itself represents an alternative strategy to starve bacteria of iron and reduce their pathogenicity. This system is particularly relevant in the context of ESKAPE pathogens, where traditional antibiotics often fail due to restricted entry.

Other names

Siderophore-mediated iron transport systemTonB-dependent transport systemBacterial iron acquisition systemFerric-siderophore transport systemSiderophore-iron uptake pathway

The primary mechanism involves the Trojan Horse strategy, where an antibacterial agent is conjugated to a siderophore or contains a siderophore-like moiety (PubMed: 31586111). This allows the drug to be actively transported into the bacterial cell via iron uptake receptors, bypassing traditional permeability barriers and achieving high intracellular concentrations (PubMed: 32103171).