Acquisition of aneuploidy provides increased fitness during the evolution of antifungal drug resistance.
Acquisition of aneuploidy provides increased fitness during the evolution of antifungal drug resistance.
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DOI：
10.1371/journal.pgen.1000705
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发表时间：
2009-10
期刊：
影响因子：
4.5
通讯作者：
Berman J
中科院分区：
文献类型：
--
作者：
Selmecki AM;Dulmage K;Cowen LE;Anderson JB;Berman J
耐药性的演变是影响临床结局的重要过程。对最广泛使用的抗真菌药物氟康唑的耐药性通常与获得性非整倍体有关。在这里，我们提供了一个纵向研究的患病率和动态的总染色体重排，包括非整倍体，在氟康唑的存在和不存在下，在一个良好的控制在体外进化实验中使用白色念珠菌，最流行的人类真菌病原体。虽然在任何非药物对照人群中均未检测到非整倍体，但在所有分析的氟康唑处理人群中，药物暴露后不久出现了等染色体5L [i（5L）]。这种等染色体与药物存在下的适应性增加有关，随着时间的推移，在独立群体中变得固定。在两个单独的情况下，较大的额外染色体组成的i（5L）连接到一个完整的染色体或染色体片段形成在暴露于药物。其他非整倍体，特别是较小染色体的三体（Chr 3 -7），出现在整个进化实验中，每个细胞多个非整倍体染色体的积累与氟康唑的最高耐药性相吻合。与许多其他微生物的情况不同，一些携带i（5L）的分离株在存在和不存在氟康唑的情况下表现出更好的适应性。非整倍体的早期出现与C.在氟康唑存在下，白色念珠菌变得更允许染色体重排和分离缺陷。 C.白色念珠菌是最普遍的人类真菌病原体，其通过遗传改变获得对氟康唑的抗性，所述遗传改变通常包括染色体或染色体臂数目的改变（非整倍性）。在这里，我们证明，染色体重排导致增加基因剂量是主要手段获得性耐药的抗真菌药物氟康唑在复制的实验种群的C。白色念珠菌一种特殊的非整倍体，即等染色体5L，由两个拷贝的Chr 5左臂组成，发生频率高，在氟康唑暴露后不久即可检测到。在某些群体中非整倍体的早期出现与C。在氟康唑存在下，白色念珠菌变得更允许染色体重排和分离缺陷。结果表明，C.白色念珠菌基因组具有高度可塑性，这意味着暴露于抗真菌药物诱导基因组重组事件，其中一些在药物存在下提供适应性优势。
The evolution of drug resistance is an important process that affects clinical outcomes. Resistance to fluconazole, the most widely used antifungal, is often associated with acquired aneuploidy. Here we provide a longitudinal study of the prevalence and dynamics of gross chromosomal rearrangements, including aneuploidy, in the presence and absence of fluconazole during a well-controlled in vitro evolution experiment using Candida albicans, the most prevalent human fungal pathogen. While no aneuploidy was detected in any of the no-drug control populations, in all fluconazole-treated populations analyzed an isochromosome 5L [i(5L)] appeared soon after drug exposure. This isochromosome was associated with increased fitness in the presence of drug and, over time, became fixed in independent populations. In two separate cases, larger supernumerary chromosomes composed of i(5L) attached to an intact chromosome or chromosome fragment formed during exposure to the drug. Other aneuploidies, particularly trisomies of the smaller chromosomes (Chr3–7), appeared throughout the evolution experiment, and the accumulation of multiple aneuploid chromosomes per cell coincided with the highest resistance to fluconazole. Unlike the case in many other organisms, some isolates carrying i(5L) exhibited improved fitness in the presence, as well as in the absence, of fluconazole. The early appearance of aneuploidy is consistent with a model in which C. albicans becomes more permissive of chromosome rearrangements and segregation defects in the presence of fluconazole. C. albicans, the most prevalent human fungal pathogen, acquires resistance to fluconazole by genetic alterations that often include changes in the number of chromosomes or chromosome arms (aneuploidy). Here we demonstrate that chromosomal rearrangements resulting in increased gene dosage are the predominant means of acquired resistance to the antifungal drug fluconazole in replicated experimental populations of C. albicans. A specific aneuploidy, isochromosome 5L, which is composed of two copies of the left arm of Chr5, occurs with high frequency and is detectable soon after fluconazole exposure. The early appearance of aneuploidy in some populations is consistent with a model in which C. albicans becomes more permissive of chromosome rearrangements and segregation defects in the presence of fluconazole. The results presented here indicate that the C. albicans genome is highly plastic and imply that exposure to an antifungal drug induces genome reorganization events, some of which provide a fitness advantage in the presence of drug.
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影响因子：
3.2
作者：
Cowen, LE;Sanglard, D;Kohn, LM
通讯作者：
Kohn, LM
影响因子：
11.4
作者：
Bennett, RJ;Johnson, AD
通讯作者：
Johnson, AD
影响因子：
4.2
作者：
Hamza OJ;Matee MI;Moshi MJ;Simon EN;Mugusi F;Mikx FH;Helderman WH;Rijs AJ;van der Ven AJ;Verweij PE
通讯作者：
Verweij PE
影响因子：
3.3
作者：
Anderson, JB;Sirjusingh, C;Ricker, N
通讯作者：
Ricker, N
DOI：
10.1073/pnas.102291099
发表时间：
2002-07-09
影响因子：
11.1
作者：
Cowen, LE;Nantel, A;Anderson, JB
通讯作者：
Anderson, JB