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Published on: February 23, 2024
The iron chelator deferasirox protects mice from mucormycosis through iron starvation
Ashraf S Ibrahim1, Teclegiorgis Gebermariam, Yue Fu
1Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA. ibrahim@labiomed.org
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.
Insights
Deferasirox, an iron chelator, shows promise in treating mucormycosis, a fungal infection with high mortality. This study demonstrates its effectiveness in vitro and in animal models, suggesting potential as an adjunctive therapy.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Mucormycosis presents a high mortality rate (≥50%) despite existing treatments.
- Elevated serum iron levels are linked to increased susceptibility to mucormycosis.
- Iron availability is crucial in the pathogenesis of various infections.
Purpose of the Study:
- To evaluate deferasirox, an FDA-approved iron chelator, as a potential treatment for mucormycosis.
- To assess the efficacy of deferasirox against clinical isolates of Mucorales.
- To investigate deferasirox's therapeutic potential in preclinical models of mucormycosis.
Main Methods:
- In vitro assessment of deferasirox's iron-chelating activity and antifungal (cidal) effects against Rhizopus oryzae and Mucorales isolates.
- In vivo studies using diabetic ketoacidotic or neutropenic mouse models of mucormycosis.
- Evaluation of deferasirox as a monotherapy and in combination with liposomal amphotericin B.
Main Results:
- Deferasirox exhibited potent in vitro cidal activity against 28/29 Mucorales clinical isolates at sub-therapeutic concentrations.
- In vivo, deferasirox significantly improved survival and reduced fungal burden in infected mice, comparable to liposomal amphotericin B.
- Combination therapy with deferasirox and liposomal amphotericin B demonstrated synergistic improvements in survival and fungal clearance.
Conclusions:
- Deferasirox is a highly effective treatment for mucormycosis, demonstrating both in vitro and in vivo efficacy.
- Deferasirox enhances the host inflammatory response and shows synergistic effects with liposomal amphotericin B.
- Clinical trials investigating deferasirox as an adjunctive therapy for mucormycosis are warranted, with potential applications in other iron-dependent infections.
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