近平滑念珠菌唑类药物体内获得/体外诱导耐药机制多组学研究

近平滑念珠菌成为国内引起念珠菌血症第一位的菌株，已经出现对唑类药物耐药菌株，基本无其他药物代替，因此唑类耐药近平滑念珠菌感染导致临床后果严重，而目前国内外对其耐药机制的研究基本空白。本研究将通过回顾性收集并研究体内获得性耐药菌株（我们拥有丰富的临床真菌感染菌株库进行筛选），并前瞻性研究体外三种唑类药物诱导耐药过程，探索不同唑类药物耐药产生的区别和相互关系，包括每种药物耐药产生的时间、是否会对其他唑类药物产生影响等，得到的结论将帮助临床更好的选择抗真菌药物、制定合理疗程和剂量，预防耐药的产生。对前部分研究筛选出的遗传背景一致的体内获得和体外诱导菌株通过多组学研究进行耐药机制筛查，并对筛查出的基因、转录及蛋白水平的差异进行验证，阐明近平滑念珠菌对唑类药物耐药以及药物间交叉耐药的主要分子机制，为快速筛查耐药机制筛选靶点、新药的研发和传统药物的改造创新提供理论依据。这将具有重大的临床意义和科学意义

Candida parapsilosis has become the most important Candida species causing candidemia, and the isolates resistant to azole drugs have emerged. Because there is limited antifungal drug for treatment of C. parapsilosis, the outcome for patients infected with resistant isolates are usually poor. However, there is little research on the mechanism of azole resistance in C. parapsilosis. In the present study, we will collect the acquired resistant isolates in vivo from the fungal surveillance programs in China, and analyzed the process of the resistance emergence by review of clinical histories. In addition, we will also induce the wide isolates to become resistance to three azoles in vitro, as well as analyzing the characteristics of each azole drug and the interactions between these drugs. The conclusion by analysis will help the doctors give more proper antifungal treatment to patients. After that, we will do research on resistance mechanisms on the matched susceptible and resistant isolates by genomics, transcriptomics, and proteomics studies. Then, we will confirm the changes in resistant isolates from aspect of DNA, RNA and proteins after bioinformatics analysis. By describing the molecular resistance mechanisms of C. parapsilosis to azole drugs, we will provide important references for the designation of new antifungal drugs, as well as the reformation of previous drugs, which is of great clinical and scientific values.