Synergic effects of tacrolimus and azole antifungal agents against azole-resistant Candida albicans strains
Synergic effects of tacrolimus and azole antifungal agents against azole-resistant Candida albicans strains
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DOI：
10.1093/jac/42.6.747
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发表时间：
1998-12-01
影响因子：
5.2
通讯作者：
Kohno, S
中科院分区：
文献类型：
--
作者：
Maesaki, S;Marichal, P;Kohno, S
我们通过比较[(3)H]伊曲康唑的积累，研究了他克莫司和唑类抗真菌药物联合使用对唑类抗性白色念珠菌菌株的影响。表达CDR1的抗性菌株C26比表达CaMDR的抗性菌株C40或唑敏感菌株B2630积累更少的伊曲康唑。表达CDR1的酿酒酵母突变体DSY415显示氟康唑和伊曲康唑的积累显着减少。表达 CaMDR 的酿酒酵母突变体 DSY416 也表现出较低的氟康唑积累，但伊曲康唑则没有。添加叠氮化钠（一种电子传递链抑制剂）仅在 C26 菌株中增加了伊曲康唑的细胞内积累，而在 C40 或 B2630 菌株中则没有增加。添加他克莫司（一种多药耐药蛋白抑制剂）导致 C26 菌株中伊曲康唑积累的最高增加。伊曲康唑和他克莫司的组合在唑类抗性白色念珠菌菌株中具有协同作用。在 C26 菌株中，与他克莫司联合使用时，伊曲康唑的 MIC 从 >8 mg/L 降至 0.5 mg/L。我们的结果表明，白色念珠菌中的两种多药耐药表型（由 CDR1 和 CaMDR 基因编码）对唑类抗真菌药物具有不同的底物特异性，并且他克莫司和唑类抗真菌药物的组合可有效对抗唑类抗性白色念珠菌菌株。
We investigated the effects of combining tacrolimus and azole antifungal agents in azole-resistant strains of Candida albicans by comparing the accumulation of [(3)H]itraconazole. The CDR1-expressing resistant strain C26 accumulated less itraconazole than the CaMDR-expressing resistant strain C40 or the azole-sensitive strain B2630. A CDR1-expressing Saccharomyces cerevisiae mutant, DSY415, showed si marked reduction in the accumulation of both fluconazole and itraconazole. A CaMDR-expressing S. cerevisiae mutant, DSY416, also showed lower accumulation of fluconazole, but not of itracconazole. The addition of sodium azide, an electron-transport chain inhibitor, increased the intracellular accumulation of itraconazole only in the C26 strain, and not in the C40 or B2630 strains. Addition of tacrolimus, an inhibitor of multidrug resistance proteins, resulted ire the highest increase in itraconazole accumulation in the C26 strain. The combination of itraconazole and tacrolimus was synergic in azole-resistant C. albicans strains. In the C26 strain, the MIC of itraconazole decreased from >8 to 0.5 mg/L when combined with tacrolimus. Our results showed that two multidrug resistance phenotypes (encoded by the CDR1 and CaMDR genes) in C. albicans have different substrate specificity for azole antifungal agents and that a combination of tacrolimus and azole antifungal agents is effective against azole-resistant strains of C. albicans.