Marr K A, Lyons C N, Rustad T R, Bowden R A, White T C
Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Antimicrob Agents Chemother. 1998 Oct;42(10):2584-9. doi: 10.1128/AAC.42.10.2584.
Fluconazole-resistant Candida albicans, a cause of recurrent oropharyngeal candidiasis in patients with human immunodeficiency virus infection, has recently emerged as a cause of candidiasis in patients receiving cancer chemotherapy and marrow transplantation (MT). In this study, we performed detailed molecular analyses of a series of C. albicans isolates from an MT patient who developed disseminated candidiasis caused by an azole-resistant strain 2 weeks after initiation of fluconazole prophylaxis (K. A. Marr, T. C. White, J. A. H. vanBurik, and R. A. Bowden, Clin. Infect. Dis. 25:908-910, 1997). DNA sequence analysis of the gene (ERG11) for the azole target enzyme, lanosterol demethylase, revealed no difference between sensitive and resistant isolates. A sterol biosynthesis assay revealed no difference in sterol intermediates between the sensitive and resistant isolates. Northern blotting, performed to quantify mRNA levels of genes encoding enzymes in the ergosterol biosynthesis pathway (ERG7, ERG9, and ERG11) and genes encoding efflux pumps (MDR1, ABC1, YCF, and CDR), revealed that azole resistance in this series is associated with increased mRNA levels for members of the ATP binding cassette (ABC) transporter superfamily, CDR genes. Serial growth of resistant isolates in azole-free media resulted in an increased susceptibility to azole drugs and corresponding decreased mRNA levels for the CDR genes. These results suggest that C. albicans can become transiently resistant to azole drugs rapidly after exposure to fluconazole, in association with increased expression of ABC transporter efflux pumps.
耐氟康唑白色念珠菌是人类免疫缺陷病毒感染患者复发性口咽念珠菌病的病因，最近已成为接受癌症化疗和骨髓移植（MT）患者念珠菌病的病因。在本研究中，我们对一名MT患者的一系列白色念珠菌分离株进行了详细的分子分析，该患者在开始氟康唑预防治疗2周后发生了由耐唑菌株引起的播散性念珠菌病（K. A. Marr、T. C. White、J. A. H. vanBurik和R. A. Bowden，《临床传染病》25:908 - 910，1997）。对唑类靶酶羊毛甾醇14α - 去甲基酶的基因（ERG11）进行DNA序列分析，结果显示敏感和耐药分离株之间没有差异。甾醇生物合成测定表明，敏感和耐药分离株之间的甾醇中间体没有差异。进行Northern印迹分析以量化麦角甾醇生物合成途径中编码酶的基因（ERG7、ERG9和ERG11）以及编码外排泵的基因（MDR1、ABC1、YCF和CDR）的mRNA水平，结果显示该系列中的唑类耐药与ATP结合盒（ABC）转运蛋白超家族成员CDR基因的mRNA水平升高有关。耐药分离株在无唑培养基中的连续传代导致对唑类药物的敏感性增加，同时CDR基因的mRNA水平相应降低。这些结果表明，白色念珠菌在接触氟康唑后可迅速对唑类药物产生短暂耐药，这与ABC转运蛋白外排泵的表达增加有关。
