Deferiprone iron chelation as a novel therapy for experimental mucormycosis.
OBJECTIVE
Patients treated with the iron chelator deferoxamine are known to be more susceptible to mucormycosis. However, while deferoxamine is an iron chelator from the perspective of the human host, deferoxamine actually serves as a siderophore, delivering free iron to Rhizopus oryzae, the major cause of mucormycosis. Other iron chelators, including deferiprone, which do not deliver iron to R. oryzae have been described. We therefore sought to determine whether iron-chelation therapy with deferiprone would effectively treat mucormycosis.


METHODS
In vitro MIC and minimum fungicidal concentration (MFC) of the iron chelator, deferiprone, for R. oryzae were determined by microdilution assay. In addition, we compared the efficacy of deferiprone with that of liposomal amphotericin B (LAmB) in treating mucormycosis in diabetic ketoacidotic mice.


RESULTS
Deferiprone demonstrated static activity against R. oryzae at 24 h, but showed cidality at 48 h of incubation. Deferiprone was as effective as LAmB at improving survival and decreasing brain fungal burden, and both drugs were more effective than placebo in non-iron-overloaded animals. Administration of free iron with deferiprone reversed protection, confirming that the mechanism of protection was iron chelation.


CONCLUSIONS
Iron chelation is a promising, novel therapeutic strategy for refractory mucormycosis infections. Further studies are warranted to evaluate combination antifungal/iron chelation therapy and to evaluate the efficacy of other iron-chelating agents.
Ibrahim
Ashraf S
AS
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. ibrahim@labiomed.org
Edwards
John E
JE
Fu
Yue
Y
Spellberg
Brad
B
D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D000077543:Deferiprone; D016883:Diabetic Ketoacidosis / Q000382:microbiology; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009091:Mucormycosis / Q000188:drug therapy* / Q000382:microbiology; D011728:Pyridones / Q000494:pharmacology*; D012233:Rhizopus / Q000187:drug effects* / Q000302:isolation & purification
D000935:Antifungal Agents; D007502:Iron Chelating Agents; D011728:Pyridones; C068538:liposomal amphotericin B; D000077543:Deferiprone; D000666:Amphotericin B