白念珠菌是人体内最主要的机会性致病真菌，大部分真菌侵袭性感染都是由白念珠菌所引起的。卡泊芬净是目前广泛使用的一种棘白菌素类抗真菌药，但耐药菌的出现造成严重的治疗障碍。通过对白念珠菌突变体文库的筛选，我们发现cdc43缺失株对卡泊芬净高度敏感，而且在耐药菌株中缺失CDC43会使其丧失对卡泊芬净的抗性，显示出Cdc43可能成为对抗临床耐药的作用靶标。CDC43编码异戊烯化酶GGTase1的β亚基，前期结果表明GGTase1对β-1,3葡聚糖合成酶调控亚基Rho1的异戊烯化修饰在调控药物敏感性中发挥了重要作用。本课题将通过遗传和生化等手段阐明GGTase1的作用机制及其调控药物敏感性的功能在念珠菌属中的保守性，明确GGTase1抑制剂与卡泊芬净联合用药对念珠菌属耐药菌株的杀菌活性，并在动物模型中检测疗效。本研究将为对抗念珠菌属卡泊芬净耐药菌的侵袭性感染提供新靶标，有望成为逆转临床耐药的治疗手段。

Candida albicans is the most prevalent opportunistic pathogenic fungus in human. It is the most common cause of invasive fungal infections. Caspofungin, an antifungal drug of the echinocandin class, is widely used in the treatment of invasive Candida infections. However, the emergence of echinocandin-resistant candidasis has become a serious problem. Through screening the mutant library of C. albicans, we found that cdc43 mutant is hypersensitive to caspofungin. Moreover, deletion of CDC43 in the echinocandin-resistant cells results in sensitivity to caspofungin, suggesting that Cdc43 could be a drug target for reducing clinical resistance. CDC43 encodes the β subunit of Geranylgeranyltransferase 1 (GGTase1). Our results indicate that the geranylgeranylation of Rho1, the regulatory subunit of β-1,3-glucan synthase, by GGTase1 plays an important role in the regulation of drug susceptibility. This project will elucidate the mechanism of GGTase1 and its functional conservation in drug susceptibility in Candida species by genetic and biochemical means. Also, we will determine whether the inhibitors of GGTase 1 potentiate the activity of caspofungin to kill echinocandin-resistant strains of Candida species. Furthermore, the therapeutic effect will be tested in animal models. This study will provide a new drug target for echinocandin-resistant candidasis, and hopefully become a therapeutic method to reverse clinical resistance.