Competitive Fitness of Fluconazole-Resistant Clinical Candida albicans Strains
Competitive Fitness of Fluconazole-Resistant Clinical Candida albicans Strains
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DOI：
10.1128/aac.00584-17
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发表时间：
2017-07-01
影响因子：
4.9
通讯作者：
Morschhaeuser, Joachim
中科院分区：
文献类型：
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作者：
Popp, Christina;Hampe, Irene A. I.;Morschhaeuser, Joachim
致病性酵母菌白色念珠菌可对广泛使用的抗真菌剂氟康唑产生耐药性，氟康唑抑制麦角甾醇的生物合成。耐药性通常由转录因子Mrr1和Tac1的功能获得性突变引起，这导致多药外排泵的组成性过表达，以及Upc 2，这导致麦角固醇生物合成基因的组成性过表达。然而，由这些转录因子的过度活跃形式引起的基因表达失调也降低了在不存在药物的情况下细胞的适应性。探讨临床耐氟康唑的念珠菌是否存在耐药。白念珠菌分离株克服了耐药的适应度成本，我们评估了白念珠菌分离株的相对适应度。在这些转录因子中含有耐药突变的白色念珠菌分离株与来自相同患者的匹配药物敏感分离株竞争。在不含氟康唑的丰富培养基中，大多数氟康唑耐药菌株被相应的药物敏感菌株所竞争。另一方面，在这些条件下，MRR 1中具有功能获得性突变的一些耐药分离株没有表现出降低的适应性。在播散性念珠菌病小鼠模型中，四分之三的氟康唑耐药临床分离株未表现出明显的适应性缺陷。然而，所有四个氟康唑耐药菌株在小鼠模型中的胃肠道定植相匹配的敏感菌株的竞争，表明在体内健身的耐药性的影响取决于宿主生态位。总的来说，我们的研究结果表明，在C。白色念珠菌不容易治疗，特别是当需要适当控制基因表达以成功适应哺乳动物宿主内的生活时。
The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis. Resistance is often caused by gain-of-function mutations in the transcription factors Mrr1 and Tac1, which result in constitutive overexpression of multidrug efflux pumps, and Upc2, which result in constitutive overexpression of ergosterol biosynthesis genes. However, the deregulated gene expression that is caused by hyperactive forms of these transcription factors also reduces the fitness of the cells in the absence of the drug. To investigate whether fluconazole-resistant clinical C. albicans isolates have overcome the fitness costs of drug resistance, we assessed the relative fitness of C. albicans isolates containing resistance mutations in these transcription factors in competition with matched drug-susceptible isolates from the same patients. Most of the fluconazole-resistant isolates were outcompeted by the corresponding drug-susceptible isolates when grown in rich medium without fluconazole. On the other hand, some resistant isolates with gain-of-function mutations in MRR1 did not exhibit reduced fitness under these conditions. In a mouse model of disseminated candidiasis, three out of four tested fluconazole-resistant clinical isolates did not exhibit a significant fitness defect. However, all four fluconazole-resistant isolates were outcompeted by the matched susceptible isolates in a mouse model of gastrointestinal colonization, demonstrating that the effects of drug resistance on in vivo fitness depend on the host niche. Collectively, our results indicate that the fitness costs of drug resistance in C. albicans are not easily remediated, especially when proper control of gene expression is required for successful adaptation to life within a mammalian host.