CgPDR1 gain‐of‐function mutations lead to azole‐resistance and increased adhesion in clinical Candida glabrata strains
CgPDR1 gain‐of‐function mutations lead to azole‐resistance and increased adhesion in clinical Candida glabrata strains
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DOI：
10.1111/myc.12756
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发表时间：
2018-04
期刊：
影响因子：
4.9
通讯作者：
Qi Ni;Chen Wang;Yuan Tian;Danfeng Dong;Cen Jiang;E. Mao;Yibing Peng
中科院分区：
文献类型：
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作者：
Qi Ni;Chen Wang;Yuan Tian;Danfeng Dong;Cen Jiang;E. Mao;Yibing Peng
近年来，光滑念珠菌已成为一种威胁健康的病原体，并且念珠菌对抗真菌药物的耐药性不断上升。光滑常导致临床治疗失败。目的研究4株临床分离菌在抗真菌治疗前后的耐药性和粘附能力的变化。进行了序列分析、基因破坏、药物敏感性、粘附试验和真实的实时定量PCR。唑类敏感菌株在抗真菌治疗后获得唑类耐药。通过序列分析发现CgPDR 1中的4个功能获得性（GOF）突变，即G1099D、G346D、L344S和P927S，最后一个为首次报道。在CgPDR 1中携带GOF突变的菌株中，CDR1、CDR2和SNQ2外排泵基因表达水平升高，导致唑类药物敏感性降低。具有不同GOF突变的CgPDR1等位基因显示出不同的药物相关基因表达谱。CgPDR1GOF突变导致外排泵表达水平以菌株背景独立的方式增加。过度活跃的Pdr1G1099D和Pdr1P927S通过上调EPA1转录显示出菌株背景依赖性增加的对宿主细胞的粘附。有趣的是，药物转运蛋白基因的表达水平并不总是与粘附素EPA1基因的表达水平相对应。CgPDR1的GOF突变赋予了临床菌株的耐药性和增加的粘附性，可能赋予了C. glabrata具有增加的活力和致病性。
Recently, Candida glabrata has emerged as a health‐threatening pathogen and the rising resistance to antifungal agent in C. glabrata often leads to clinical treatment failure. To investigate the evolution of drug resistance and adherence ability in four paired clinical isolates collected before and after antifungal treatment. Sequence analysis, gene disruption, drug‐susceptibility, adhesion tests and real‐time quantitative PCR were performed. The azole‐susceptible strains acquired azole resistance after antifungal therapy. Four gain‐of‐function (GOF) mutations in CgPDR1 were revealed by sequence analysis, namely G1099D, G346D, L344S and P927S, the last being reported for the first time. CDR1, CDR2 and SNQ2 efflux pump gene expression levels were elevated in strains harbouring GOF mutations in CgPDR1, resulting in decreased azole susceptibility. CgPDR1 alleles with distinct GOF mutations displayed different expression profiles for the drug‐related genes. CgPDR1GOF mutations led to increased efflux pumps expression levels in a strain background independent way. Hyperactive Pdr1G1099D and Pdr1P927S displayed strain background‐dependent increased adherence to host cells via upregulation of EPA1 transcription. Interestingly, the drug transporter gene expression levels did not always correspond with that of the adhesin EPA1 gene. GOF mutations in CgPDR1 conferred drug resistance and increased adherence in the clinical strains, possibly endowing C. glabrata with increased viability and pathogenicity.