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Background: Mucormycosis is a destructive invasive mold infection afflicting patients with diabetes and hematologic malignancies. Patients with diabetes are often treated with statins, which have been shown to have antifungal properties. We sought to examine the effects of statins on Rhizopus oryzae, a common cause of mucormycosis., Methods: Clinical strains of R. oryzae were exposed to lovastatin, atorvastatin, and simvastatin and the minimum inhibitory concentrations (MICs) were determined. R. oryzae germination, DNA fragmentation, susceptibility to oxidative stress, and ability to damage endothelial cells were assessed. We further investigated the impact of exposure to lovastatin on the virulence of R. oryzae, Results: All statins had MICs of >64 µg/mL against R. oryzae Exposure of R. oryzae to statins decreased germling formation, induced DNA fragmentation, and attenuated damage to endothelial cells independently of the expression of GRP78 and CotH. Additionally, R. oryzae exposed to lovastatin showed macroscopic loss of melanin, yielded increased susceptibility to the oxidative agent peroxide, and had attenuated virulence in both fly and mouse models of mucormycosis., Conclusions: Exposure of R. oryzae to statins at concentrations below their MICs decreased virulence both in vitro and in vivo. Further investigation is warranted into the use of statins as adjunctive therapy in mucormycosis., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

In an experimental model of obesity and hyperglycemia in Drosophila melanogaster we studied the effect of diet modification and administration of metformin on systemic infection with Rhizopus, a common cause of mucormycosis in diabetic patients. Female Wt-type Drosophila flies were fed regular (RF) or high-fat diet (HFD; 30% coconut oil) food with or without metformin for 48 h and then injected with R. oryzae. Survival rates, glucose and triglyceride levels were compared between 1) normal-weight flies (RF), 2) obese flies (HFD), 3) obese flies fed with RF, 4) flies continuously fed on HFD + metformin, 5) flies fed on HFD + metformin, then transferred to RF, and 6) obese flies administered metformin after infection [corrected].Glucose levels were compared across groups of non-infected flies and across groups of infected flies. Survival was significantly decreased (P = 0.003) in obese flies, while post-infection glucose levels were significantly increased (P = 0.0001), compared to normal-weight flies. Diet and administration of metformin led to weight loss, normalized glucose levels during infection, and were associated with decreased mortality and tissue fungal burden. In conclusion, diet and metformin help control infection-associated hyperglycemia and improve survival in Drosophila flies with mucormycosis. Fly models of obesity bear intriguing similarities to the pathophysiology of insulin resistance and diabetes in humans, and can provide new insights into the pathogenesis and treatment of infections in obese and diabetic patients.

Mortality associated with mucormycosis remains high despite current antifungals. Iron-starvation strategies have been shown to have promising activity against Mucorales. We hypothesized that iron starvation enhances apoptosis in Rhizopus oryzae. Apoptosis was characterized in R. oryzae transformed with RNAi plasmid targeting FTR1 expression (iron permease mutant) or empty plasmid grown in iron rich (0.125% FeCl3) and iron depleted media (YNB+1mM ferrozine and 1 mM ascorbic acid). Increased apoptosis was observed with dihydrorhodamine-123 and rhodamine-123 staining in the iron starved mutant FTR1 when compared to empty plasmid, followed by increased extracellular ATP levels. In addition, DNA fragmentation and metacaspase activity were prominent in FTR1. In contrast, Rhizopus strains grown in iron-rich medium displayed minimal apoptosis. Our results demonstrate a metacaspase dependent apoptotic process in iron deprived condition and further support the role of iron starvation strategies as an adjunct treatment for mucormycosis, a mechanism by which iron starvation affects R. oryzae. [ABSTRACT FROM AUTHOR]