Bacterial iron–sulfur cluster-containing enzymes and iron metabolism pathways

Bacterial iron–sulfur (Fe-S) cluster-containing enzymes and iron metabolism pathways represent a complex network of proteins and processes essential for bacterial survival, virulence, and adaptation to host environments. Fe-S clusters are vital inorganic cofactors that facilitate electron transfer, catalysis, and environmental sensing in enzymes involved in the TCA cycle, respiration, and DNA repair (Ezraty et al., 2017, Nature Reviews Microbiology). Because iron is scarce in the host due to nutritional immunity, bacteria utilize specialized iron acquisition systems, including the secretion of high-affinity siderophores and the expression of dedicated transporters, often regulated by the Ferric Uptake Regulator (Fur) protein (Kramer et al., 2020, Nature Reviews Microbiology). These pathways are increasingly recognized as viable therapeutic targets, particularly for addressing multi-drug resistant (MDR) pathogens. Pharmacological interventions include iron mimetics like gallium, which substitutes for iron in Fe-S clusters and enzymes to induce lethal metabolic dysfunction (Goss et al., 2018, Science Translational Medicine), and siderophore-antibiotic conjugates such as Cefiderocol that utilize bacterial iron transporters to bypass outer membrane barriers (Simner et al., 2020, Clinical Infectious Diseases). Targeting these systems offers a strategy to starve bacteria of essential nutrients or disrupt fundamental metabolic processes, though challenges remain regarding potential cross-reactivity with host iron-dependent pathways (Choi & Skaar, 2022, Nature Reviews Microbiology).

Other names

Bacterial iron homeostasisFe-S cluster biogenesisSiderophore uptake systemFerric uptake regulation (Fur) system

Siderophore-mediated antibiotic delivery (Trojan horse), competitive inhibition of iron-dependent enzymes, disruption of Fe-S cluster assembly and stability, and inhibition of iron uptake transporters.