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Title: The iron chelator deferasirox protects mice from mucormycosis through iron starvation

Author
item IBRAHIM, ASHRAF - UCLA MEDICAL CENTER
item GEBERMARIAM, TECHEFIORGIS - UCLA MEDICAL CENTER
item FU, YUE - UCLA MEDICAL CENTER
item LIN, LIN - UCLA MEDICAL CENTER
item HUSSEINY, MOHAMED - UCLA MEDICAL CENTER
item FRENCH, SAMUEL - UCLA MEDICAL CENTER
item SCHWARTZ, JULIE - CHARLES RIVER LAB
item Skory, Christopher - Chris
item EDWARDS, JOHN - UCLA MEDICAL CENTER
item SPELLBERG, BRAD - UCLA MEDICAL CENTER

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/13/2007
Publication Date: 9/4/2007
Citation: Ibrahim, A.S., Gebermariam, T., Fu, Y., Lin, L., Husseiny, M.I., French, S.W., Schwartz, J., Skory, C.D., Edwards, J.E., Spellberg, B.J. 2007. The iron chelator deferasirox protects mice from mucormycosis through iron starvation. Journal of Clinical Investigation. 117(9):2649-2657.

Interpretive Summary: The filamentous fungus Rhizopus oryzae is used in numerous industrial/food applications and is an organism that is generally regarded as being safe. However, it is the most prevalent cause of mucormycosis, a life-threatening infection that usually afflicts patients with debilitated immune systems or those with specific underlying abnormalities. Uptake of iron by the fungus appears to be closely linked to the infection process and considerable research has focused on this mechanism. In this work, we demonstrate that deferasirox, a medication recently approved for use in humans by the United States (US) Food and Drug Administration (FDA), is a highly effective treatment for mucormycosis. Deferasirox works by chelating or binding free iron in the patient, thereby making it unavailable for the organism. It not only inhibited growth of the Rhizopus, but also had the ability to effectively kill the fungus in 28 of 29 clinical isolates. Deferasirox was even more effective at improving survival in animal models when combined with other treatments. This work is expected to enhance current treatment options and significantly increase the likelihood of survival for this type of infection.

Technical Abstract: Clinical and animal model data indicate that the presence of elevated available serum iron predisposes the host to mucormycosis. Here we demonstrate that deferasirox, an iron chelator recently approved for use in humans by the United States (US) Food and Drug Administration (FDA), is a highly effective treatment for mucormycosis. Deferasirox effectively chelated iron from Rhizopus oryzae, and demonstrated cidal activity in vitro against 28 of 29 clinical isolates of Mucorales at concentrations well below achievable serum levels. When administered to diabetic ketoacidotic or neutropenic mice with disseminated mucormycosis, deferasirox significantly improved survival and decreased tissue fungal burden to a degree similar to liposomal amphotericin B. In addition to its direct antifungal effect, deferasirox treatment also enhanced the host inflammatory response to mucormycosis compared to mice treated with saturating iron or placebo. Most importantly, deferasirox synergistically improved survival and reduced tissue fungal burden when combined with liposomal amphotericin B. These data support clinical investigation of adjunctive deferasirox therapy to improve the abysmal outcomes of mucormycosis with current therapy.