Akins Robert A
Wayne State University School of Medicine, Departments of Biochemistry & Molecular Biology, 540 East Canfield, Detroit, Michigan 48201, USA.
Med Mycol. 2005 Jun;43(4):285-318. doi: 10.1080/13693780500138971.
Much progress has been made in the last decade in identifying genes responsible for antifungal resistance in Candida albicans. Attention has focused on five major C. albicans genes: ABC transporter genes CDR1 and CDR2, major facilitator efflux gene MDR1, and ergosterol biosynthesis genes ERG11 and ERG3. Resistance involves mutations in 14C-lanosterol demethylase, targeted by fluconazole (FLZ) and encoded by ERG11, and mutations that up-regulate efflux genes that probably efflux the antifungals. Mutations that affect ERG3 mutations have been understudied as mechanism resistance among clinical isolates. In vitro resistance in clinical isolates typically involves step-wise mutations affecting more than one of these genes, and often unidentified genes. Different approaches are needed to identify these other genes. Very little is understood about reversible adaptive resistance of C. albicans despite its potential clinical significance; most clinical failures to control infections other than oropharyngeal candidiasis (OPC) occur with in vitro susceptible strains. Tolerance of C. albicans to azoles has been attributed to the calcineurin stress-response pathway, offering new potential targets for next generation antifungals. Recent studies have identified genes that regulate CDR1 or ERG genes. The focus of this review is C. albicans, although information on Saccharomyces cerevisiae or Candida glabrata is provided in areas in where Candida research is underdeveloped. With the completion of the C. albicans genomic sequence, and new methods for high throughput gene overexpression and disruption, rapid progress towards understanding the regulation of resistance, novel resistance mechanisms, and adaptive resistance is expected in the near future.
在过去十年中，在鉴定白色念珠菌中抗真菌耐药性相关基因方面取得了很大进展。研究重点集中在五个主要的白色念珠菌基因上：ABC转运蛋白基因CDR1和CDR2、主要易化子外排基因MDR1以及麦角甾醇生物合成基因ERG11和ERG3。耐药性涉及14C-羊毛甾醇脱甲基酶的突变，该酶是氟康唑（FLZ）的作用靶点，由ERG11编码，以及上调可能使抗真菌药物外排的外排基因的突变。影响ERG3的突变作为临床分离株中的耐药机制尚未得到充分研究。临床分离株的体外耐药性通常涉及影响这些基因中多个基因的逐步突变，并且常常涉及未鉴定的基因。需要采用不同方法来鉴定这些其他基因。尽管白色念珠菌的可逆适应性耐药具有潜在临床意义，但人们对此了解甚少；除口咽念珠菌病（OPC）外，大多数控制感染的临床失败病例都发生在体外敏感菌株中。白色念珠菌对唑类药物的耐受性归因于钙调神经磷酸酶应激反应途径，这为新一代抗真菌药物提供了新的潜在靶点。最近的研究已经鉴定出调节CDR1或ERG基因的基因。本综述的重点是白色念珠菌，不过在念珠菌研究尚不充分的领域也提供了酿酒酵母或光滑念珠菌的相关信息。随着白色念珠菌基因组序列的完成，以及高通量基因过表达和破坏的新方法的出现，预计在不久的将来，在理解耐药性调控、新的耐药机制和适应性耐药方面将取得快速进展。
