Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata
Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata
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DOI：
10.1128/aac.39.8.1696
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发表时间：
1995-08
影响因子：
4.9
通讯作者：
T. Parkinson;D. Falconer;C. Hitchcock
中科院分区：
文献类型：
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作者：
T. Parkinson;D. Falconer;C. Hitchcock
我们从一例感染的光滑念珠菌中报道了氟康唑耐药的机制，其中治疗前和治疗后的分离株可用于比较。耐药的后处理分离株与其他耐药酵母菌一样，对酮康唑和伊曲康唑具有交叉耐药性。耐药性是由于[~3H]氟康唑累积水平的减少，而不是麦角甾醇生物合成水平的变化。对代谢或呼吸抑制剂的研究表明，这种现象是能量依赖的药物外流的结果，而不是内流的障碍。由于能量依赖的外排是细菌、酵母和哺乳动物细胞多药耐药的特征，我们研究了氟康唑耐药是由多药耐药类型机制介导的可能性。白念珠菌多药耐药蛋白的底物苯菌灵与氟康唑竞争从光滑念珠菌分离株的外排，这与这些化合物的共同外排机制一致。相比之下，多药耐药蛋白的其他标准底物或抑制剂对氟康唑的外排没有影响。总之，我们已经确定氟康唑的能量依赖性外排，可能通过多药耐药类型的转运体，是光滑念珠菌对氟康唑耐药的机制。
We report on the mechanism of fluconazole resistance in Candida glabrata from a case of infection in which pre- and posttreatment isolates were available for comparison. The resistant, posttreatment isolate was cross-resistant to ketoconazole and itraconazole, in common with other azole-resistant yeasts. Resistance was due to reduced levels of accumulation of [3H]fluconazole rather than to changes at the level of ergosterol biosynthesis. Studies with metabolic or respiratory inhibitors showed that this phenomenon was a consequence of energy-dependent drug efflux, as opposed to a barrier to influx. Since energy-dependent efflux is a characteristic of multidrug resistance in bacteria, yeasts, and mammalian cells, we investigated the possibility that fluconazole resistance is mediated by a multidrug resistance-type mechanism. Benomyl, a substrate for the Candida albicans multidrug resistance protein, showed competition with fluconazole for efflux from resistance C. glabrata isolates, consistent with a common efflux mechanism for these compounds. By contrast, other standard substrates or inhibitors of multidrug resistance proteins had no effect on fluconazole efflux. In conclusion, we have identified energy-dependent efflux of fluconazole, possibly via a multidrug resistance-type transporter, as the mechanism of resistance to fluconazole in C. glabrata.