The iron chelator deferasirox protects mice from mucormycosis through iron starvation
Ashraf S. Ibrahim, … , John E. Edwards Jr., Brad J. Spellberg
Ashraf S. Ibrahim, … , John E. Edwards Jr., Brad J. Spellberg
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2649-2657. https://doi.org/10.1172/JCI32338.
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Research Article Microbiology

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

Abstract

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.

Authors

Ashraf S. Ibrahim, Teclegiorgis Gebermariam, Yue Fu, Lin Lin,, Mohamed I. Husseiny, Samuel W. French, Julie Schwartz, Christopher D. Skory, John E. Edwards Jr., Brad J. Spellberg

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Figure 2

Deferasirox protects diabetic ketoacidotic mice from hematogenously disseminated R. oryzae infection.

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Deferasirox protects diabetic ketoacidotic mice from hematogenously diss...
Mice infected via the tail vein were treated with placebo (hydroxypropylcellulose carrier), deferasirox, or deferasirox plus iron (FeCl3, 10 mg/kg) to reverse the effect of iron chelation. (A) Survival of mice (n ≥ 7 per group) infected with R. oryzae 99-892 (2.2 × 104 spores) and treated with various doses of deferasirox. (B) Brain and kidney fungal burden of mice (n = 11 per group) infected with R. oryzae 99-892 (4.2 × 104 spores) and treated with placebo, deferasirox (10 mg/kg twice daily), or deferasirox plus iron. Organs were harvested on day 4 after mice received 3 daily treatments. Data are displayed as median ± interquartile ranges. The y axis reflects the lower limit of detection of the assay. (C) H&E-stained kidney sections of mice infected with R. oryzae 99-892 and treated with deferasirox, deferasirox plus ferric chloride, or placebo as described in B. Arrows indicate R. oryzae hyphae in tissue. Sections are representative of findings throughout organs in all mice in the respective groups. Original magnification, ×400. (D) Survival of diabetic ketoacidotic mice (n = 24 from 3 separate experiments with similar results) infected via the tail vein with R. oryzae 99-880 (average inoculum, 1.3 × 103 spores) and 24 hours later treated with 10 mg/kg deferasirox twice daily for 7 days. *P < 0.05 for survival and †P < 0.002 for tissue fungal burden compared with placebo or deferasirox plus ferric chloride.