IRON UPTAKE FROM FERRIOXAMINE AND FROM FERRIRHIZOFERRIN BY GERMINATING SPORES OF RHIZOPUS-MICROSPORUS

Mucormycosis caused by the fungus Rhizopus has been documented in iron overloaded patients and more particularly in dialysis patients, both when treated with desferrioxamine B (DFO). This iron and aluminium chelator is thought to play a role in the pathogenesis of this infection. We therefore investigated in vitro the cellular pharmacology of iron chelated by DFO in the fungus Rhizopus. In a medium, designed for fungal cultivation, Rhizopus microsporus var rhizopodiformis takes up iron from ferric-DFO complex (Fe-55.DFO) and from Fe-55.rhizoferrin, the siderophore synthesized and secreted by Rhizopus [Drechsel et al., Biol. Metals 4: 238-243, 1991]. In both cases, iron accumulation is partially saturable with the duration of exposure and the chelator concentration. Fe.DFO binds to Rhizopus; iron becomes trapped and remains associated with the fungus, whereas the iron-depleted siderophore is released in the extracellular medium. In a medium designed for mammalian cell cultivation and in the absence of human serum, the fungal iron accumulation both from Fe-55.DFO and from Fe-55.rhizoferrin is proportional to the chelator concentration. Human serum at 40% does not influence the iron accumulation from Fe.DFO but it significantly affects that from Fe.rhizoferrin which, in the presence of serum, only occurs at concentration > 5 mu M. This difference finds its explanation in the iron transfer observed between Fe.rhizoferrin and seric apotransferrin, the latter making the metal unavailable to Rhizopus. By contrast, no iron transfer takes place between Fe.DFO and apotransferrin, allowing fungal iron utilization from this complex, even at very low concentrations. The iron uptake, being inhibited by NaN3 and KCN, is energy-dependent; being inhibited by bipyridyl, it requires prior reduction of ferric iron; being unaffected by the covalent linkage of Fe.DFO to albumin, it does not require the entry of Fe.DFO within the fungus. These in vitro results strongly suggest that, upon administration of DFO to iron overloaded or dialysis patients, the formed Fe.DFO is efficiently used as an iron source by Rhizopus, even in the presence of serum apotransferrin or rhizoferrin. The consequent promotion of the growth of Rhizopus helps explain the increased risk of mucormycosis in DFO-treated patients.