The antifungal activity of statins has been explored for both yeast and filamentous fungi. Unfortunately, the in vitro minimum inhibitory concentrations (MIC) for many statins are at supraphysiological levels. Although the primary target of statins is inhibition of sterol biosynthesis, another potential outcome of statin therapy is downregulation of Ras pathway signaling via inhibition of isoprenoid synthesis and subsequent mislocalization of Ras proteins. Cerivastatin has sterol lowering effects at concentrations 100x less than that of currently available statins. Although pulled from the market in 2001 due to toxicity, cerivastatin continues to be investigated for its anti-inflammatory, immunomodulatory and anticarcinogenic effects. In this study, we examined for the first time the antifungal activity of cerivastatin. We further explored the impact of Ras mutations on the sensitivity of Aspergillus fumigatus to cerivastatin.
The MIC of rosuvastatin and cerivastatin was determined for ATCC strains of Candida albicans, Candida krusei, Cryptococcus neoformans; wild type Saccharomyces cerevisiae; and 3 strains of Aspergillus fumigatus: wild type (H237), inactivated RasA (RasA) and over activated Ras (RasAG17V). MIC analyses were performed following approved CLSI guidelines.
Compared to rosuvastatin, cerivastatin displayed significantly lower MIC values for all strains tested, except for Cryptococcus neoformans. A. fumigatus displayed the lowest cerivastatin MIC of all fungi tested, suggesting that filamentous fungal growth is especially sensitive to statin therapy. In support of this, cerivastatin treatment caused stunted A. fumigatus hyphae with aberrant hyphal morphology and hyper-branching. Of the A. fumigatus strains tested, the overactivated RasA mutant (RasAG17V) showed high level of cerivastatin sensitivity (MIC 0.0038 µg/ml) when compared to the wild type (MIC 0.015 µg/ml). In contrast, deletion of RasA caused resistance to cerivastatin (MIC 0.06 µg/ml).
Together, these results suggest that cerivastatin displays powerful antifungal activity and that alteration of Ras signaling affects outcome of statin therapy.
J. Fortwendel, None