摘要
唑类抗真菌药物广泛用于临床和农业。唑类药物通过与羊毛甾醇14α‐去甲基化酶(Erg11p/Cyp51)结合,抑制麦角甾醇合成,同时导致有毒甾醇积累。真菌可快速在转录水平上对唑类药物胁迫作出响应而导致耐药性,尤其是唑类药物外排泵基因和麦角甾醇合成相关基因表达的上调。农业和临床上绝大多数唑类药物耐药菌株的形成都是由麦角甾醇合成基因和唑类药物外排泵表达的变化或是突变所致。一些转录因子(如Pdr1p、Pdr3p、Upc2p、Yap1p、Tac1p、Mrr1p、CCG‐8)和信号通路(如c AMP途径、PKC‐MAPK途径、HOG MAPK途径、钙调磷酸酶途径)均参与对药物外排泵基因和麦角甾醇合成基因等的调控,影响唑类药物耐药性。针对于这些调控因子设计的抑制剂将有助于提高唑类药物的治疗效果。本文概述了唑类药物的抑菌机制、真菌对唑类药物耐药性形成的原因、真菌对唑类药物适应性响应机理,并对未来此领域的热点和方向进行了展望。
Antifungal azoles, which inhibit lanosterol 14α-demethylase （Erg11p/Cyp51） in ergosterol biosynthesis, are widely used n clinic and agriculture. However, fungi can ra especially genes encoding azole efflux pumps pidly and ncrease expression of a number of genes in response to azole stress, azole targets, and become resistant to azoles. The overexpression or mutations on genes involved in ergosterol biosynthesis or drug efflux are the main reason for azole resistance in the majority of azole-resistant isolates. Transcription factors, including Pdrlp, Pdr3p, Upc2p, Yaplp, Taclp, Mrrlp, and CCG-8, and signaling pathways, including cAMP pathway, PKC-MAPK, HOG MAPK pathways, and calcinerin pathway, were found to be involved in azole stress response by regulating genes such as ergosterol biosynthesis genes and/or azole efflux pump genes. Inhibitors targeting these regulators will help to improve the therapeutic effect of azoles. This article reviewed the antifungal mechanisms of azoles, the causes of azole resistance and fungal adaptive mechanisms to azoles. The future research directions were also proposed
出处
《菌物学报》
CAS
CSCD
北大核心
2015年第5期927-941,共15页
Mycosystema
基金
国家自然科学基金(31371986)
关键词
唑类药物
耐药性
真菌
azoles, drug resistance, fungi
