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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Categories: 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 1

Deferasirox induces the expression of rFTR1.

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Deferasirox induces the expression of rFTR1. (A) RT-PCR expression of rF...
(A) RT-PCR expression of rFTR1 from R. oryzae mycelia incubated in iron-replete, iron chelation (deferasirox), or reversal of iron chelation (deferasirox saturated with ferric chloride) conditions. Expression of the 18S rDNA was included to verify the quality of RNA extraction. (B) Diagram demonstrating the strategy for constructing R. oryzae GFP expression vector. Promoter denotes either rFTR1p or ACT1p. (C) GFP expression in R. oryzae driven by rFTR1p or ACT1p as determined by confocal images and flow cytometry of R. oryzae grown in iron-replete medium or medium containing deferasirox alone or deferasirox saturated with ferric chloride. GFP expression was revealed by green fluorescent cells by confocal microscopy, and the percentage of fluorescent cells in channel FL1 (y axis) by flow cytometry. In contrast to GFP under the control of the ACT1p, which was constitutively expressed regardless of growth conditions, GFP under the control of the rFTR1p was expressed only in the presence of iron chelation conditions (deferasirox [Def]).