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.

Iron starvation induces apoptosis in rhizopus oryzae in vitro

“…On the contrary, deferasirox demonstrates cidal activity against Mucorales in vitro and treatment of Rhizopus-infected mice with deferasirox markedly improves survival, reduces fungal burden in target organs, and enhances the host inflammatory response to mucormycosis, further reinforcing the role of iron in pathogenesis. 1 These results were also corroborated by our findings that deferasirox protects Drosophila from mucormycosis infection. 6 Fu et al 7 cloned the high-affinity iron permease (FTR1) of R. oryzae, which is a primary effector for organism ability to acquire iron in iron-limited environments such as those found in susceptible hosts.…”

“…All of these factors contribute to higher mortaility in patients with mucormycosis and make the results of this small pilot trial hard to interpret. 17 Only a large, Phase III trial, potentially enrolling only diabetic or corticosteroid-treated patients (since animal model and case studies suggested a benefit of using deferasirox in this patient populations), 1,18 and excluding cancer/neutropenia patients, could further elucidate the safety and efficacy of initial, adjunctive deferasirox for the treatment of mucormycosis.…”

“…1,2 Unfortunately, despite surgical debridement and systemic antifungal therapy, the overall mortality rate for mucormycosis remains high and may approach 100% in patients with disseminated disease, or persistent neutropenia. 2,3,4 Thus, new strategies to prevent and treat mucormycosis are urgently needed.…”

“…5 Ibrahim et al 1 found that the iron chelator deferasirox, unlike the deferoxamine, does not act as an iron siderophore for Rhizopus. On the contrary, deferasirox demonstrates cidal activity against Mucorales in vitro and treatment of Rhizopus-infected mice with deferasirox markedly improves survival, reduces fungal burden in target organs, and enhances the host inflammatory response to mucormycosis, further reinforcing the role of iron in pathogenesis.…”

“…Iron starvation causes the rapid expression of FTR1 in R. oryzae, while excess iron in the form of ferric chloride reduces this expression. 1,3 Apoptosis has been studied in many higher eukaryotes but also have been observed in lower eukaryotes, including yeasts and filamentous fungi. [8][9][10][11] Rhizopus exhibit apoptotic markers that are similar to those of mammalian cells, including phosphatidylserine externalization, reactive oxygen species (ROS) accumulation, mitochondrial membrane potential dissipation, and DNA condensation and fragmentation.…”