The iron chelator deferasirox protects mice from mucormycosis through iron starvation.
Mucormycosis causes mortality in at least 50% of cases despite current first-line therapies. Clinical and animal 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 US 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 clinically achievable serum levels. When administered to diabetic ketoacidotic or neutropenic mice with mucormycosis, deferasirox significantly improved survival and decreased tissue fungal burden, with an efficacy similar to that of liposomal amphotericin B. Deferasirox treatment also enhanced the host inflammatory response to mucormycosis. 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 poor outcomes of mucormycosis with current therapy. As iron availability is integral to the pathogenesis of other infections (e.g., tuberculosis, malaria), broader investigation of deferasirox as an antiinfective treatment is warranted.
Ibrahim
Ashraf S
AS
Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA. ibrahim@labiomed.org
Gebermariam
Teclegiorgis
T
Fu
Yue
Y
Lin
Lin
L
Husseiny
Mohamed I
MI
French
Samuel W
SW
Schwartz
Julie
J
Skory
Christopher D
CD
Edwards
John E
JE
Spellberg
Brad J
BJ
D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D001565:Benzoates / Q000627:therapeutic use*; D000077588:Deferasirox; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000473:pathology; D004359:Drug Therapy, Combination; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D008081:Liposomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009090:Mucorales / Q000187:drug effects / Q000276:immunology; D009091:Mucormycosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D014230:Triazoles / Q000627:therapeutic use*