The genetic basis of fluconazole resistance development in Candida albicans
The genetic basis of fluconazole resistance development in Candida albicans
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DOI：
10.1016/s0925-4439(02)00087-x
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发表时间：
2002-07-18
影响因子：
6.2
通讯作者：
Morschhäuser, J
中科院分区：
文献类型：
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作者：
Morschhäuser, J
机会性真菌病原体白色念珠菌感染广泛使用抗真菌药物氟康唑治疗，该药物可抑制麦角甾醇（真菌质膜中的主要甾醇）的生物合成。耐氟康唑白色念珠菌菌株的出现是获得性免疫缺陷综合征（AIDS）患者复发性口咽念珠菌病（OPC）长期治疗后的一个重要问题。耐药性可能是由于甾醇生物合成的改变、药物靶标酶甾醇 14α-去甲基酶 (14DM) 的突变（降低其对氟康唑的亲和力）、编码 14DM 的 ERG11 基因表达增加或编码 ABC 转运蛋白 (CDR1/CDR2) 或主要促进子 (MDR1) 超家族膜转运蛋白的基因过度表达而引起的。不同的机制经常结合在一起，导致氟康唑耐药性随着时间的推移逐步发展。 MDR1 基因在氟康唑敏感的白色念珠菌菌株的体外生长过程中不转录或几乎不转录，但在许多氟康唑耐药的临床分离株中过度表达，导致细胞内氟康唑积累减少。耐药菌株中该基因的激活是由迄今未知的反式调节因子的突变引起的，由此产生的MDR1高水平表达导致对除氟康唑之外的其他有毒化合物产生耐药性。耐药白色念珠菌分离株中 MDR1 基因的两个等位基因的破坏消除了它们对这些药物的耐药性，这提供了 MDR1 介导白色念珠菌多重耐药性的遗传证据。 (C) 2002 Elsevier Science B.V 保留所有权利。
Infections by the opportunistic fungal pathogen Candida albicans are widely treated with the antifurgal agent fluconazole that inhibits the biosynthesis of ergosterol, the major sterol in the fungal plasma membrane. The emergence of fluconazole-resistant C albicans strains is a significant problem after long-term treatment of recurrent oropharyngeal candidiasis (OPC) in acquired immunodeficiency syndrome (AIDS) patients. Resistance can be caused by alterations in sterol biosynthesis, by mutations in the drug target enzyme, sterol 14alpha-demethylase (14DM), which lower its affinity for fluconazole, by increased expression of the ERG11 gene encoding 14DM, or by overexpression of genes coding for membrane transport proteins of the ABC transporter (CDR1/CDR2) or the major facilitator (MDR1) superfamilies. Different mechanisms are frequently combined to result in a stepwise development of fluconazole resistance over time. The MDR1 gene is not or barely transcribed during growth in vitro in fluconazole-susceptible C albicans strains, but overexpressed in many fluconazole-resistant clinical isolates, resulting in reduced intracellular fluconazole accumulation. The activation of the gene in resistant isolates is caused by mutations in as yet unknown trans-regulatory factors, and the resulting constitutive high level of MDR1 expression causes resistance to other toxic compounds in addition to fluconazole. Disruption of both alleles of the MDR1 gene in resistant C. albicans isolates abolishes their resistance to these drugs, providing genetic evidence that MDR1 mediates multidrug resistance in C. albicans. (C) 2002 Elsevier Science B.V All rights reserved.