Mucormycosis is a life-threatening infection caused by certain members of the fungal
order Mucorales, with increased incidence in recent years. Individuals with untreated
diabetes mellitus, and patients treated with deferoxamine are particularly susceptible
to this infection. Elevated free iron concentrations in serum contribute to the development
of mucormycosis. Pathogenic fungi have evolved multiple mechanisms to acquire and
utilize free iron or extract it from the various iron-binding molecules within the
host. The utilization of hydroxamate siderophores as xenosiderophores may contribute
to the development of mucormycosis. The genome of Mucor lusitanicus encodes one Sit1
siderophore transporter. In this study, the role of the sit1 gene was characterized
by generating knockout mutants using CRISPR-Cas9. Relative transcript level of the
sit1 gene significantly increased in the presence of deferoxamine- and deferasirox-iron
complexes. Lack of sit1 resulted in altered germination of spores and growth ability,
and decreased virulence. Furthermore, absence of the gene caused elevated transcript
levels of a ferric reductase (FRE), a low-affinity iron permease (FET4) and a copper
dependent iron oxidase (FET3). Our result suggests that expressions of the genes involved
in iron uptake affect each other. The lack of Sit1 resulted in an increased transcript
level of the FRE3 gene, which may be able to reduce iron from the siderophore-iron
complex. The reduced and liberated iron may be then taken up by activated FET4a. This
study highlights the significance of understanding the iron acquisition mechanisms
of pathogenic fungi to develop effective treatments for fungal infections.
