Iron acquisition strategies in pathogenic fungi

Abstract

Iron plays a crucial role in various biological processes, including enzyme function, DNA replication, energy production, oxygen transport, lipid, and carbon metabolism. Although it is abundant in the Earth's crust, its bioavailability is restricted by the insolubility of ferric iron (Fe³⁺) and the auto-oxidation of ferrous iron (Fe²⁺) in oxygen-rich environments. This limitation poses significant challenges for all organisms, including fungi, which have developed intricate mechanisms for iron acquisition and utilization. These mechanisms include reductive iron uptake, siderophore production/transport, and heme utilization. Fungi employ a variety of enzymes-such as ferric reductases, ferroxidases, permeases, and transporters-to regulate intracellular iron levels effectively. The challenge is heightened for pathogenic fungi during infection, as they must compete with the host's iron-binding proteins like transferrin and lactoferrin, which sequester iron to restrict pathogen growth. This review delves into the iron acquisition strategies of medically important fungi, emphasizing the roles of reductive iron uptake and siderophore pathways. Understanding these mechanisms is vital for enhancing our knowledge of fungal pathogenesis and developing effective treatments. By targeting these iron acquisition processes, new antifungal therapies can be formulated more effectively to combat fungal infections.

Keywords: antifungal therapy; fungal infections; iron acquisition; iron metabolism; iron-binding proteins; siderophores.

Fig 1

Comparison of iron acquisition, storage, and use by select pathogenic fungi and mammals. Pathogenic fungi have evolved methods of iron acquisition to facilitate growth in the host, including host-heme utilization, siderophore iron scavenging, and the reductive iron assimilation pathway, which includes ferric reductase, iron permease, and ferroxidase. Fungi store iron in vacuoles or specific storage siderophores. Mammals primarily obtain iron through dietary sources, but recycling strategies include senescent erythrocyte endocytosis and heme/hemoglobin recycling through CD91 and CD163, respectively. Mammals regulate iron through transferrin and ferritin, which can prevent iron from being used by microbes, although fungal siderophores have been shown to be able to scavenge iron from transferrin.

Fig 2

(A) General hydroxamate siderophore synthesis pathway. L-ornithine is hydroxylated by SidA, followed by acetylation by SidL. The peptide is synthesized by peptide synthetase SidC, yielding, in this example, desferri-ferricrocin. (B) Chemical structures of key iron-chelating agents and related compounds: deferoxamine (also called desferrioxamine B), a trihydroxamic acid siderophore; deferiprone, a bidentate hydroxypyridinone chelator; deferasirox, a tridentate chelator; and protoporphyrin, a precursor in heme biosynthesis.