PDR16-mediated azole resistance in Candida albicans
PDR16-mediated azole resistance in Candida albicans
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DOI：
10.1111/j.1365-2958.2006.05196.x
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发表时间：
2006-06-01
影响因子：
3.6
通讯作者：
Raymond, Martine
中科院分区：
文献类型：
--
作者：
Saidane, Saloua;Weber, Sandra;Raymond, Martine
许多白色念珠菌唑类耐药（A（R））临床分离株过表达编码ATP结合盒家族同源多药转运蛋白的CDR 1和CDR 2基因。我们在这里表明，这些菌株也过表达PDR 16基因，直向同源的酿酒酵母PDR 16编码的Sec 14 p家族的磷脂酰肌醇转移蛋白。据报道，S。酿酒酵母pdr 16 Delta突变体对唑类药物敏感性增高，提示C.白色念珠菌PDR 16可能与这些分离株的唑类耐药有关。为了解决这个问题，我们使用麦考酚酸抗性翻转策略，在过表达三个基因的A（R）临床菌株中删除了PDR 16的两个等位基因。我们的结果显示，纯合的pdr 16 Delta/pdr 16 Delta突变体对唑类的抗性比亲本菌株低大约两倍，而在突变体中重新引入PDR 16的拷贝恢复了唑类抗性，表明该基因有助于细胞的A（R）表型。此外，PDR 16在唑敏感的（A（S））C.白色念珠菌和S.酿酒酵母菌株的唑类抗性增加了约两倍，表明在没有额外的分子改变的情况下，增加剂量的Pdr 16 p可以赋予低水平的唑类抗性。综上所述，这些结果表明PDR 16在C.白色念珠菌唑类耐药。
Many Candida albicans azole-resistant (A(R)) clinical isolates overexpress the CDR1 and CDR2 genes encoding homologous multidrug transporters of the ATP-binding cassette family. We show here that these strains also overexpress the PDR16 gene, the orthologue of Saccharomyces cerevisiae PDR16 encoding a phosphatidylinositol transfer protein of the Sec14p family. It has been reported that S. cerevisiae pdr16 Delta mutants are hypersusceptible to azoles, suggesting that C. albicans PDR16 may contribute to azole resistance in these isolates. To address this question, we deleted both alleles of PDR16 in an A(R) clinical strain overexpressing the three genes, using the mycophenolic acid resistance flipper strategy. Our results show that the homozygous pdr16 Delta/pdr16 Delta mutant is approximately twofold less resistant to azoles than the parental strain whereas reintroducing a copy of PDR16 in the mutant restored azole resistance, demonstrating that this gene contributes to the A(R) phenotype of the cells. In addition, overexpression of PDR16 in azole-susceptible (A(S)) C. albicans and S. cerevisiae strains increased azole resistance by about twofold, indicating that an increased dosage of Pdr16p can confer low levels of azole resistance in the absence of additional molecular alterations. Taken together, these results demonstrate that PDR16 plays a role in C. albicans azole resistance.