新型抗白念珠菌药物的作用靶点

Target sites of new anti-Candida albicands agents

随着氮唑类药物广泛应用,白念珠菌耐药现象快速发展,已出现药物间交叉耐药,对临床治疗带来严重威胁。近年来相继提出了许多抗白念珠菌药物作用的新靶点并成功开发出一些活性强大,疗效确切的抗真菌药,如以真菌细胞壁为靶点开发出棘白菌素类药物卡泊芬净、米卡芬净等,该类药物主要抑制β-葡聚糖合成酶,体外对氟康唑耐药的念珠菌属及真菌生物被膜表现出强大的抗菌活性,又由于β-葡聚糖合成酶在哺乳类动物细胞内不存在,故具有高效低毒的临床效果,是一极具前途的新型抗真菌药;以真菌细胞膜为靶点开发出Histatin类药物,虽然作用机制目前还不完全明了,但其作用不同于临床常用的多烯类和氮唑类,并已经发现Histatin5对两性霉素B和氮唑类耐药的念珠菌有效,并且对非白念珠菌如光滑念珠菌、克柔氏念株菌、隐球菌等也有杀灭作用;通过对植物药物的研究发现黄连素和丁香罗勒(Ocimum gratissimumL.)具有较强大的抗真菌活性,其中黄连素提取物小檗碱对24-MST抑制作用强大,并对菌丝生长形式抑制作用强于酵母生长形式。增强白念珠菌对药物敏感性的新方法包括改变细胞膜成分、改变某些基因、利用光灭活作用、使用抗菌药增敏剂以及抗真菌药物的联合使用等。本文就近年来开发的新型抗真菌药以及提出的抗白念珠菌药物作用新靶点进行综述。

With the wide use of azoles, drug tolerance and cross tolerance of Candida albicands has seriously hampered the clinical treatments of Candida albicands. New antifungal agents （potent and effective） have been developed over the past years based on the discovery of many new target sites of Candida albicands. For example, Echinocandins （caspofungin and micafungin）, aiming at the cell wall of Candida albicands, showed strong antifungal activities to fluconazole resistant candidas and fungal biofilm. Moreover, because β-glucan synthase does not exist on the cell membrane of mammalian cells, Echinocandins has a low toxicity and a promising clinical future. Though the mechanism of Histatin （targeting fungal membrane） is not clear, it has strong activity not only on candida resistant of polyene and azole, but also to Candida parapsilosis, Candida krusei and Cryptococcus neoformans. Berberine and Ocimum gratissimum L. were also found to have prominent anti-fungi activities. Ber- berine extract can intensively inhibit 24-SMT in a dose-depended manner; besides, it has more potent inhibitory activity against the growth of mycelia than against that of yeast. Various new methods can be used to increase the susceptibility of Candida albicands to antifungal agents, such as altering fungi membrane composition, changing some genes, adopting the photodynamic inactivation method, employing hypersensitization agents and combining antifungal agents. This article reviews the newly-developed antifungal agents and newly-proposed target sites of Candida albicands.