title: Pravastatin inhibits farnesol production in Candida albicans and improves survival in a mouse model of systemic candidiasis.
abstract: Candidemia remains a major cause of morbidity and mortality, especially in immunocompromised patients. A strategy of reducing virulence and virulence factors of Candida spp. is an attractive approach for the treatment of serious infections caused by these yeasts. Recently, farnesol has been reported to be a quorum-sensing autoinducer, as well as a virulence factor of C. albicans. In the present study, we examined the effects of pravastatin, a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor on the in vitro production of farnesol. In addition, the synergistic effects of pravastatin with fluconazole (FLC) were examined in a mouse model of systemic infections. In vitro experiments demonstrated that pravastatin had synergistic activity with FLC as judged by fractional inhibitory concentration index (FICI) and suppression of farnesol production at sub-minimum inhibitory concentrations. Furthermore, significant improvement of survival in systemic infection models was shown with pravastatin supplementation. The survival benefits of pravastatin were correlated with reductions of fungal burden. These data suggest the potential of pravastatin as a supportive therapy against C. albicans infections. Synergistic antifungal activity and suppression of HMG-CoA reductase-associated Candida virulence factors, including farnesol, may explain, at least in part, the in vivo efficacy of pravastatin.
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Tashiro
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kimura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tateda
authors.forename: Tomoo
authors.initials: T
authors.lastname: Saga
authors.forename: Akira
authors.initials: A
authors.lastname: Ohno
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ishii
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tashiro
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism*; D002177:Candidiasis / Q000401:mortality*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D005204:Farnesol / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D017035:Pravastatin / Q000008:administration & dosage* / Q000494:pharmacology; D016019:Survival Analysis; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D037521:Virulence Factors; D005204:Farnesol; D017035:Pravastatin