Effects of statins on growth, sterol levels and azoles activity in Saccharomyces cerevisiae and Candida utilis strains.

CABRAL, MARÍA E; SAMPIETRO, DIEGO A; FARIÑA, JULIA I; FIGUEROA, LUCÍA IC

Kiev, Ukraine

Congreso; ICY2008, 12th International Congress on Yeasts; 2008

International Commission of yeasts

Statins can inhibit the de novo synthesis of sterols by competitive inhibition of HMG-CoA reductase, which catalyzes the rate limiting step of sterols biosynthesis. Besides, it is known that lovastatin and its analogs present ability to block the synthesis of intermediate products in the mevalonate pathway. Therefore statins may have significant influence on critical cellular functions being able to induce apoptosis. Thus, they might be applied to tumor-like or fibro-proliferative diseases treatment. Azoles, by inhibiting cytochrome P-450 sterol C-14 a-demethylation are widely used for many fungal infections treatment. It is thought that synergic fungicidal effects could occur between azoles and statins. The advantage of this synergism is the low hydrophobicity and toxicity of statins for humans, as compared with azole-family drugs. In this work rapid and simple techniques were developed to evaluate the effects of statins on growth, sterol levels and azoles effectiveness in Candida utilis Pr1-2  and Saccharomyces cerevisiae ATCC 32051. A bioassay was developed in order to detect inhibition haloes on YNB-agar-embedded yeast cells. The effect of statins (lovastatin, simvastatin, pravastatin, atorvastatin and rosuvastatin) or statins plus azoles (miconazole, clotrimazole and ketoconazole) was assessed after 12 h incubation. Yeast growth inhibition as consequence of sterol biosynthesis blockage was confirmed by adding exogenous ergosterol as counterevidence. According to results, S. cerevisiae was shown to be more susceptible to statins than C. utilis. Additionally, total free sterols from yeast cultures grown with or without 0·1 g/L statins were detected by TLC. The relative intensity of ergosterol band was analyzed with Image J program. Synergism was evaluated by combining a sub-inhibitory level of statins plus a minimum inhibitory concentration of azoles (MIC). The observed different degree of synergism between some of the proposed statins and azoles may allow lower azoles doses when administered in conjunction with statins for fungal infections treatment. Likewise, the proposed bioassay could be also useful as a screening method for evaluating statins production in fungal cultures.