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Dialysis patients with chronic renal failure receiving deferoxamine for treating iron overload are uniquely predisposed for mucormycosis, which is most often caused by  Rhizopus oryzae . Although the deferoxamine siderophore is not secreted by  Mucorales , previous studies established that  Rhizopus  species utilize iron from ferrioxamine (iron-rich form of deferoxamine). Here we determined that the CBS domain proteins of Fob1 and Fob2 act as receptors on the cell surface of  R .  oryzae  during iron uptake from ferrioxamine. Fob1 and Fob2 cell surface expression was induced in the presence of ferrioxamine and bound radiolabeled ferrioxamine. A  R .  oryzae  strain with targeted reduced Fob1/Fob2 expression was impaired for iron uptake, germinating, and growing on medium with ferrioxamine as the sole source of iron. This strain also exhibited reduced virulence in a deferoxamine-treated, but not the diabetic ketoacidotic (DKA), mouse model of mucormycosis. The mechanism by which  R .  oryzae  obtains iron from ferrioxamine involves the reductase/permease uptake system since the growth on ferrioxamine supplemented medium is associated with elevated reductase activity and the use of the ferrous chelator bathophenanthroline disulfonate abrogates iron uptake and growth on medium supplemented with ferrioxamine as a sole source of iron. Finally,  R .  oryzae  mutants with reduced copies of the high affinity iron permease ( FTR1 ) or with decreased  FTR1  expression had an impaired iron uptake from ferrioxamine  in vitro  and reduced virulence in the deferoxamine-treated mouse model of mucormycosis. These two receptors appear to be conserved in  Mucorales , and can be the subject of future novel therapy to maintain the use of deferoxamine for treating iron-overload.

Fob1 and Fob2 Proteins Are Virulence Determinants of Rhizopus oryzae via Facilitating Iron Uptake from Ferrioxamine