The role of iron and iron chelators in zygomycosis

Iron is an essential element for cell growth and development, contributing to DNA synthesis and regulating the G1-phase to S-phase transition. Moreover, iron is important for the virulence of the majority of microorganisms, and the function of the genes regulating iron uptake is coupled with the manifestations of the virulence phenotype. All fungi elaborate specific uptake mechanisms to sequester iron, and most commonly produce small molecules with high affinity for iron, the siderophores. The importance of iron appears to be particularly high for Zygomycetes, which grow abundantly in iron-rich media, and all the known predisposing factors for zygomycosis have, as a common feature, the increased availability of free iron. Among the known iron chelators, deferoxamine supports the growth of Zygomycetes because it acts as xenosiderophore, delivering iron to iron-uptaking molecules of these species. Conversely, the newer iron chelators deferiprone and deferasirox do not exhibit similar activity, apparently because they share higher affinity constants for iron and, as a result, deprive the fungi of iron, inhibiting their growth. This activity has been documented in various culture systems and in many animal models of zygomycosis, and therefore suggests that these drugs might be used as adjuvant treatment for systemic zygomycosis. There are few case reports in which the newer iron chelators have been used as antifungals, and their possible benefit must be verified in a prospective randomized trial.