Synergistic antifungal activity of statin-azole associations as witnessed by Saccharomyces cerevisiae- and Candida utilis-bioassays and ergosterol quantification

被引:41
作者
Cabral, Maria Eugenia [1 ]
Figueroa, Lucia I. C. [1 ,2 ]
Farina, Julia I. [1 ]
机构
[1] PROIMI CONICET Planta Piloto Proc Ind Microbiol, San Miguel De Tucuman, Argentina
[2] Univ Nacl Tucuman, Catedra Microbiol Super, Fac Bioquim Quim & Farm, San Miguel De Tucuman, Argentina
来源
REVISTA IBEROAMERICANA DE MICOLOGIA | 2013年 / 30卷 / 01期
关键词
Statins; Azoles; Synergism; Opportunistic yeasts; Saccharomyces cerevisiae; Candida utilis; IN-VITRO; FILAMENTOUS FUNGI; HUMAN PATHOGEN; COA REDUCTASE; FLUCONAZOLE; LOVASTATIN; ALBICANS; TOXICITY; THERAPY; EPIDEMIOLOGY;
D O I
10.1016/j.riam.2012.09.006
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Background: Frequent opportunist fungal infections and the resistance to available antifungal drugs promoted the development of new alternatives for treatment, like antifungal drug combinations. Aims: This work aimed to detect the antifungal synergism between statins and azoles by means of an agar-well diffusion bioassay with Saccharomyces cerevisiae ATCC 32051 and Candida utilis Pr1-2 as test strains. Methods: Synergistic antifungal effects were tested by simultaneously adding a sub inhibitory concentration (SIC) of statin (atorvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin) plus a minimal inhibitory concentration (MIC) of azole (clotrimazole, fluconazole, itraconazole, ketoconazole or miconazole) to yeast-embedded YNB agar plates, and a positive result corresponded to a yeast growth inhibition halo higher than that produced by the MIC of the azole alone. Yeast cell ergosterol quantification by RP-HPLC was used to confirm statin-azole synergism, and ergosterol rescue bioassays were performed for evaluating statin-induced ergosterol synthesis blockage. Results: Growth inhibition was significantly increased when clotrimazole, fluconazole, itraconazole, ketoconazole and miconazole were combined with atorvastatin, lovastatin, rosuvastatin and simvastatin. Highest growth inhibition increments were observed on S. cerevisiae (77.5%) and C utilis (43.2%) with a SIC of simvastatin plus a MIC of miconazole, i.e. 4 + 2.4 mu g/ml or 20 + 4.8 mu g/ml, respectively. Pravastatin showed almost no significant effects (0-7.6% inhibition increase). Highest interaction ratios between antifungal agents corresponded to simvastatin-miconazole combinations and were indicative of synergism. Synergism was also confirmed by the increased reduction in cellular ergosterol levels (S. cerevisiae, 40% and C utilis, 22%). Statin-induced ergosterol synthesis blockage was corroborated by means of ergosterol rescue bioassays, pravastatin being the most easily abolished inhibition whilst rosuvastatin being the most ergosterol-refractory. Conclusions: Selected statin-azole combinations might be viable alternatives for the therapeutic management of mycosis at lower administration doses or with a higher efficiency. (C) 2012 Revista lberoamericana de Micologia. Published by Elsevier Espana, S.L. All rights reserved.
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收藏
页码:31 / 38
页数:8
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