抗真菌药物在farnesol或非farnesol条件下对外阴阴道假丝酵母菌耐药性的诱导及其机制研究

Vulvovaginal candidosis is a gynecology common vaginal infections diseases, which has the characteristics of repeated attacks and difficult to be cured thoroughly in general. On the basis of the incidence and antifungal susceptibility surveillance refer to longitudinal and large sample, which isolated from patients with vulvovaginal candidiasis, and the homology analysis, we tend to study the effect and mechanism of different antifungal agents on gene induced resistance with or without farnesol in clinical or laboratory sensitive Vulvovaginal Candidiasis. Our subject want to make clear whether VVC are relapse or reinfection, and to evaluate the induced resistant ability of different antifungal drug, to compare the differences of clinical or laboratory sensitive strains in the evolution of resistance and the specific resistance mechanism in certain circumstances(in vivo or in vitro), to understand the environmental factors (in vivo or in vitro), antibiotics function and interference factors (quorum-sensing autoinducer-farnesol) impress on the treatment process and the final outcome. The purpose of the work is to provide theoretical basis on choosing more reasonable antifungal drugs to cure VVC thoroughly, and to prevent the drug resistance and recurrent of VVC candidas.

外阴阴道假丝酵母菌病（VVC）是一种妇科常见的假丝酵母菌阴道感染性疾病,具有反复发作的特点，临床中一般很难得到彻底治愈。我们前期纵向大样本检测了门诊分离VVC假丝酵母菌的药物敏感性变迁并对同患者多样本菌株进行同源性核型分析的基础上，本项目针对VVC的反复发作及耐药性问题，拟进行不同抗真菌药物对临床分离或实验室应用敏感阴道假丝酵母菌的诱导耐药性及其具体耐药机制的研究，以明确VVC反复发作是复发还是再感染，评价不同抗真菌药物诱导阴道假丝酵母菌产生耐药性的能力；比较临床或实验室敏感菌株在特定环境下（体内、体外）耐药性的发展演变和具体耐药机制差异；了解环境因素（体内、体外）、抗生素及干扰因素（群体效应信号分子）对治疗过程及其结局的影响，为更加合理选择应用抗真菌药物彻底治愈VVC，预防或减少VVC的反复发作及病原菌的耐药提供理论依据。

外阴阴道假丝酵母菌病（VVC）是一种妇科常见的假丝酵母菌阴道感染性疾病,具有反复发作的特点，临床中一般很难得到彻底治愈。我们通过大样本检测外阴阴道假丝酵母菌的药物敏感性，并对同患者多样本菌株进行同源性核型分析，体外分析不同抗真菌药物对假丝酵母菌的诱导耐药性及具体耐药机制，评价菌株群体感应信号分子farnesol 对假丝酵母菌及阴道乳杆菌的作用及具体机制。研究数据显示，当前制霉菌素是治疗VVC强有效的抗菌药物，克霉唑次之。不同抗真菌药物对假丝酵母菌的诱导耐药能力存在差异，进展相对缓慢。氟康唑耐药率增加明显相对容易诱导菌株耐药，应避免长程应用。阴道内残存旧病原菌再次侵染是VVC再发作的病原学基础，控制宿主内源性诱发因素和彻底清除病原菌是预防VVC复发的关键。Farnesol对假丝酵母菌的抑菌或杀菌活性呈浓度依赖性，其抑制白假丝酵母菌菌丝生长，涉及以碳能代谢为中心的多个代谢路径相关酶的改变，共同受表型转化信号调控因子的调节。Farnesol与抗真菌药物的联合效应机制与麦角固醇合成路径中ERG25和ERG4表达量降调相关。Farnesol 抑制假丝酵母菌的浓度并不影响乳杆菌的生长及活性，值得更加深入研究。本研究统计分析了目前当地外阴阴道假丝酵母菌的流行病学特点；明确了VVC反复发作是复发还是再感染的困惑；评价了不同抗真菌药物诱导阴道假丝酵母菌产生耐药性的能力；了解了抗生素及干扰因素（群体效应信号分子）在VVC治疗过程及其结局的影响力；并从蛋白质水平初步探索了farnesol对假丝酵母菌的作用机制。结果为更加合理选择应用抗真菌药物彻底治愈VVC，预防或减少VVC的反复发作及病原菌的耐药提供理论依据。