Overexpression of the MDR1 gene is sufficient to confer increased resistance to toxic compounds in Candida albicans
Overexpression of the MDR1 gene is sufficient to confer increased resistance to toxic compounds in Candida albicans
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DOI：
10.1128/aac.50.4.1365-1371.2006
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发表时间：
2006-04-01
影响因子：
4.9
通讯作者：
Morschhäuser, J
中科院分区：
文献类型：
--
作者：
Hiller, D;Sanglard, D;Morschhäuser, J
MDR1编码一种主要易化超家族的膜转运蛋白，其过表达是人类真菌病原体白色念珠菌对抗真菌药物氟康唑和其他有毒化合物产生耐药性的一种机制。在临床白色念珠菌分离株中，组成性MDR1 qoverexpression伴随着其他基因的上调，但尚不清楚这些额外的改变是否是Mdr1p功能和耐药性所必需的。探讨MDR1过表达是否足以使念珠菌产生耐药表型。在白色念珠菌中，我们表达了来自强ADHI启动子的MDR1基因。不表达内源性MDR1基因的白色念珠菌实验室菌株以及氟康唑耐药的临床念珠菌。白念珠菌分离株，其中内源性MDR1等位基因已被删除，并在一个匹配的氟康唑敏感的分离，从同一患者。强制MDR1过表达导致对推定的Mdr1p底物浅蓝菌素和布雷菲德菌素A的耐药性增加，并且这种耐药性不依赖于临床分离株耐药性发展过程中发生的额外改变。相反，从ADHI启动子的MDR1基因的人工表达没有增强或仅略微增强氟康唑抗性，大概是因为转化体中的Mdr1p表达水平显著低于在氟康唑抗性临床分离株中观察到的水平。这些结果表明，C.白色念珠菌足以赋予对作为该外排泵的底物的一些毒性化合物的抗性，但抗性程度取决于Mdr1p表达水平。
Overexpression of MDR1, which encodes a membrane transport protein of the major facilitator superfamily, is one mechanism by which the human fungal pathogen Candida albicans can develop increased resistance to the antifungal drug fluconazole and other toxic compounds. In clinical C albicans isolates, constitutive MDR1 qverexpression is accompanied by the upregulation of other genes, but it is not known if these additional alterations are required for Mdr1p function and drug resistance. To investigate whether MDR1 overexpression is sufficient to confer a drug-resistant phenotype in C. albicans, we expressed the MDR1 gene from the strong ADHI promoter in C. albicans laboratory strains that did not express the endogenous MDR1 gene as well as in a fluconazole-resistant clinical C. albicans isolate in which the endogenous MDR1 alleles bad been deleted and in a matched fluconazole-susceptible isolate from the same patient. Forced MDR1 overexpression resulted in increased resistance to the putative Mdr1p substrates cerulenin and brefeldin A, and this resistance did not depend on the additional alterations which occurred during drug resistance development in the clinical isolates. In contrast, artificial expression of the MDR1 gene from the ADHI promoter did not enhance or only slightly enhanced fluconazole resistance, presumably because Mdr1p expression levels in the transformants were considerably lower than those observed in the fluconazole-resistant clinical isolate. These results demonstrate that MDR1 overexpression in C. albicans is sufficient to confer resistance to some toxic compounds that are substrates of this efflux pump but that the degree of resistance depends on the Mdr1p expression level.