Background: Statins are well known inhibitors of HMG-coA reductase key to the cholesterol and ergosterol biosynthesis pathways. Since isoprenes are synthesized as a branch of this pathway, statins may also inhibit production of essential isoprenylated proteins. We report susceptibility assays for a variety of species of Candida and molds with FDA-approved statins, and synergy studies of antifungals with lovastatin. Methods: Susceptibility testing followed NCCLS guidelines. Drugs supplied as lactone precursors were first activated by heating in alcoholic NaOH. Results: Statins were inhibitory for most Candida species, but most required high concentrations (~250 μg/ml). Zocor was the most effective of the 6 tested statins (MIC 1- 30 μg/ml), except C. krusei (MIC 250). The observed hierarchy was Zocor > Fluvastatin > Lovastatin > Lipitor = Crestor > Pravastatin. Lovastatin or fluvastatin showed additive or modestly synergistic interactions with azoles, terbinafine, cyclosporin A, and the protein kinase C inhibitor chelerythrine. Among 18 mold species, there was a wide range in susceptibility to fluvastatin or lovastatin, not predicted by taxonomic status; fluvastatin was more effective overall. High susceptibility to fluvastatin did not predict susceptibility to lovastatin. For Aspergillus species, lovastatin showed no interaction with caspofungin or voriconazole, and moderate synergy with cyclosporin A. Conclusions: FDA-approved statins are effective antifungals in vitro in the μg/ml range, so are presumably not sufficiently potent, alone or combined with several antifungals, to be useful as in vivo antimicrobial agents, since statin serum concentrations only reach 10-20 ng/ml. Individual statins showed large differences in their in vitro antifungal potency, despite structural similarities. This suggests that rational, structure-based modifications to current statins have the potential to dramatically increase their antifungal activity.
Full conference title:
47th Interscience Conference on Antimicrobial agents and Chemotherapy
- ICAAC 47th