title: Statin Concentrations Below the Minimum Inhibitory Concentration Attenuate the Virulence of Rhizopus oryzae.
abstract: 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.
  
  
  
  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
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Infectious Disease, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Anne-Pauline
authors.initials: AP
authors.lastname: Bellanger
authors.affiliation: Department of Infectious Disease, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Tatara
authors.affiliation: Department of Infectious Disease, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Fazal
authors.initials: F
authors.lastname: Shirazi
authors.affiliation: Division of Infectious Disease, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.
authors.forename: Teclegiorgis
authors.initials: T
authors.lastname: Gebremariam
authors.affiliation: Department of Infectious Disease, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Albert
authors.affiliation: Department of Medical Science and Surgery, University Orsola-Malpighi, Bologna, Italy.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.affiliation: Division of Infectious Disease, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Ibrahim
authors.affiliation: Department of Infectious Disease, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000069059:Atorvastatin / Q000494:pharmacology / Q000627:therapeutic use; D004175:Diptera / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008826:Microbial Sensitivity Tests; D009091:Mucormycosis / Q000188:drug therapy*; D012233:Rhizopus / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D013172:Spores, Fungal / Q000187:drug effects; D013781:Texas; D014774:Virulence / Q000187:drug effects*
chemical_list: D000935:Antifungal Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin
keywords: Rhizopus oryzae; apoptosis; fly model; germination; murine model; statins; virulence