Evolution of drug resistance in experimental populations of Candida albicans
Evolution of drug resistance in experimental populations of Candida albicans
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DOI：
10.1128/jb.182.6.1515-1522.2000
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发表时间：
2000-03-01
影响因子：
3.2
通讯作者：
Kohn, LM
中科院分区：
文献类型：
--
作者：
Cowen, LE;Sanglard, D;Kohn, LM
在从白色念珠菌的单个药物敏感细胞建立的复制实验种群中，监测了抗真菌药物氟康唑对抑制浓度的适应性，并饲养了330代以上。在6个种群中，氟康唑的浓度维持在MIC的两倍；另外6个种群中没有添加氟康唑。用氟康唑培养的所有6个重复种群都适应了药物的存在，MIG的增加表明；没有用氟康唑生长的6个种群都没有表现出任何MIC变化。在所有通过药物进化的种群中，氟康唑耐药性的增加伴随着对酮康唑和伊曲康唑的耐药性的增加；这些种群的细胞膜中含有麦角甾醇，对两性霉素敏感。随着药物的进化，6个群体中氟康唑MIC的增加遵循不同的轨迹，这些群体获得了不同程度的耐药，与唑耐药有关的4个基因的过度表达模式不同：ATP结合盒转运蛋白基因CDR1和CDR2；编码麦角固醇生物合成途径中的唑类靶酶的基因ERG11；以及主要促进基因mdr1。在这些群体中，选择性扫描伴随着额外的基因组变化，这些变化与耐药性没有已知的关系：所检测的五个标记基因中的两个基因杂合性丧失，DNA指纹和电泳核型发生变化。这些结果表明，在白念珠菌实验种群中，机会，以赋予适应性优势的突变的形式，是对唑类耐药性进化的决定因素。
Adaptation to inhibitory concentrations of the antifungal agent fluconazole was monitored in replicated experimental populations founded from a single, drug-sensitive cell of the yeast Candida albicans and reared over 330 generations. The concentration of fluconazole was maintained at twice the MIC in six populations; no fluconazole was added to another six populations. All six replicate populations grown with fluconazole adapted to the presence of drug as indicated by an increase in MIG; none of the six populations grown without fluconazole showed any change in MIC. In all populations evolved with drug, increased fluconazole resistance was accompanied by increased resistance to ketoconazole and itraconazole; these populations contained ergosterol in their cell membranes and were amphotericin sensitive. The increase in fluconazole MIC in the six populations evolved with drug followed different trajectories, and these populations achieved different levels of resistance, with distinct overexpression patterns of four genes involved in azole resistance: the ATP-binding cassette transporter genes, CDR1 and CDR2; the gene encoding the target enzyme of the azoles in the ergosterol biosynthetic pathway, ERG11; and the major facilitator gene, MDR1. Selective sweeps in these populations were accompanied by additional genomic changes with no known relationship to drug resistance: loss of heterozygosity in two of the five marker genes assayed and alterations in DNA fingerprints and electrophoretic karyotypes. These results show that chance, in the form of mutations that confer an adaptive advantage, is a determinant in the evolution of azole drug resistance in experimental populations of C. albicans.