A proteomic approach to understanding the development of multidrug-resistant Candida albicans strains
A proteomic approach to understanding the development of multidrug-resistant Candida albicans strains
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DOI：
10.1007/s00438-004-0984-x
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发表时间：
2004-06-01
影响因子：
3.1
通讯作者：
Morschhäuser, J
中科院分区：
文献类型：
--
作者：
Kusch, H;Biswas, K;Morschhäuser, J
致病性酵母菌白色念珠菌对抗真菌剂氟康唑的耐药性通常是由编码多药外排泵（CDR 1、CDR 2或MDR 1）的基因的过表达引起的。我们采用蛋白质组学的方法，进一步了解控制外排泵表达和耐药性的调控网络。白色念珠菌。三对配对的氟康唑敏感和耐药临床念珠菌。对耐药性与MDR 1或CDR 1/2稳定活化相关的白念珠菌分离株进行蛋白质表达谱差异分析。在两个独立的MDR 1过表达菌株中，鉴定了另外的上调蛋白，其由YPR 127基因和IFD（YPL 088）基因家族的几个成员编码。所有这些都是功能未知的推定醛酮还原酶。这些蛋白在过表达CDR 1和CDR 2但不表达MDR 1的氟康唑耐药菌株中没有上调，表明C.白色念珠菌由不同的调控网络控制。为了研究YPR 127在临床分离株耐药表型中的可能作用，我们在一株C.白色念珠菌实验室菌株。此外，该基因在C.白色念珠菌实验室菌株和其中它过表达的耐药临床分离株之一中。YPR 127的强制过表达或缺失均不影响菌株对药物和其他有毒物质的敏感性，这表明控制C.白色念珠菌还控制与耐药性无关的细胞功能相关的基因。
Resistance of the pathogenic yeast Candida albicans to the antifungal agent fluconazole is often caused by the overexpression of genes that encode multidrug efflux pumps (CDR1, CDR2, or MDR1). We have undertaken a proteomic approach to gain further insight into the regulatory network controlling efflux pump expression and drug resistance in C. albicans. Three pairs of matched fluconazole-susceptible and resistant clinical C. albicans isolates, in which drug resistance correlated with stable activation of MDR1 or CDR1/2, were analyzed for differences in their protein expression profiles. In two independent, MDR1-overexpressing, strains, additional up-regulated proteins were identified, which are encoded by the YPR127 gene and several members of the IFD (YPL088) gene family. All are putative aldo-keto reductases of unknown function. These proteins were not up-regulated in a fluconazole-resistant strain that overexpressed CDRI and CDR2 but not MDR1, indicating that expression of the various efflux pumps of C. albicans is controlled by different regulatory networks. To investigate the possible role of YPR127 in the resistance phenotype of the clinical isolates, we constitutively overexpressed the gene in a C. albicans laboratory strain. In addition, the gene was deleted in a C. albicans laboratory strain and in one of the drug-resistant clinical isolates in which it was overexpressed. Neither forced overexpression nor deletion of YPR127 affected the susceptibility of the strains to drugs and other toxic substances, suggesting that the regulatory networks which control the expression of efflux pumps in C. albicans also control genes involved in cellular functions not related to drug resistance.