Genome-Wide DNA Changes Acquired by Candida albicans Caspofungin-Adapted Mutants.
Genome-Wide DNA Changes Acquired by Candida albicans Caspofungin-Adapted Mutants.
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DOI：
10.3390/microorganisms11081870
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发表时间：
2023-07-25
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
棘白菌素（ECN）类药物现在被推荐作为治疗由一种流行的真菌病原体C。白色念珠菌然而，ECN的使用增加与对ECN的耐药性上升有关。随着C.白念珠菌被认为是一个多步骤的演变，与ECN易感性降低相关的决定因素是重要的。我们最近已经确定了两组基因，无论是上调或下调的音乐会，以控制细胞壁的重塑，细胞器的ECN为目标，在实验室突变与ECN易感性降低。在这里，我们分析了这些适应突变体中的四个的全局DNA序列，以寻找与ECN易感性降低相关的DNA变化。我们发现了有限数量的112个独特的突变，代表两种替代突变途径。大约一半的突变发生在热点。大约一半的突变和热点是由ECN适应突变体共享的，尽管突变体作为独立事件出现，并且在它们的一些表型以及5号染色体的条件上不同。共有88个突变与43个开放阅读框（ORF）相关，并发生在ORF内部或ORF的1 kb内，主要是单核苷酸取代。突变发生在5′-UTR比3′-UTR更频繁，比例为1.67：1。总共16个突变映射到不是ORF的8个基因组特征：Tca 4 -4逆转录转座子; Tca 2 -7逆转录转座子; lambda-4a长末端重复序列; mu-Ra长末端重复序列; MRS-7 b主要重复序列; MRS-R主要重复序列; RB 2 -5a重复序列;和TL（CAA）亮氨酸tRNA。最后，8个突变与任何ORF或其他基因组特征无关。在非相关的药物适应性突变体中重复发生单核苷酸取代强烈表明这些DNA变化伴随着药物适应性，并可能影响ECN的易感性，从而作为促进FKS 1经典突变导致ECN耐药性演变的因素。
Drugs from the echinocandin (ECN) class are now recommended ‘front-line’ treatments of infections caused by a prevailing fungal pathogen, C. albicans. However, the increased use of ECNs is associated with a rising resistance to ECNs. As the acquisition of ECN resistance in C. albicans is viewed as a multistep evolution, determining factors that are associated with the decreased ECN susceptibility is of importance. We have recently identified two cohorts of genes that are either up- or downregulated in concert in order to control remodeling of cell wall, an organelle targeted by ECNs, in laboratory mutants with decreased ECN susceptibility. Here, we profiled the global DNA sequence of four of these adapted mutants in search of DNA changes that are associated with decreased ECN susceptibility. We find a limited number of 112 unique mutations representing two alternative mutational pathways. Approximately half of the mutations occurred as hotspots. Approximately half of mutations and hotspots were shared by ECN-adapted mutants despite the mutants arising as independent events and differing in some of their phenotypes, as well as in condition of chromosome 5. A total of 88 mutations are associated with 43 open reading frames (ORFs) and occurred inside of an ORF or within 1 kb of an ORF, predominantly as single-nucleotide substitution. Mutations occurred more often in the 5′-UTR than in the 3′-UTR by a 1.67:1 ratio. A total of 16 mutations mapped to eight genomic features that were not ORFs: Tca4-4 retrotransposon; Tca2-7 retrotransposon; lambda-4a long terminal repeat; mu-Ra long terminal repeat; MRS-7b Major Repeat Sequence; MRS-R Major Repeat Sequence; RB2-5a repeat sequence; and tL (CAA) leucine tRNA. Finally, eight mutations are not associated with any ORF or other genomic feature. Repeated occurrence of single-nucleotide substitutions in non-related drug-adapted mutants strongly indicates that these DNA changes are accompanying drug adaptation and could possibly influence ECN susceptibility, thus serving as factors facilitating evolution of ECN drug resistance due to classical mutations in FKS1.
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影响因子：
5.8
作者：
Li, Heng
通讯作者：
Li, Heng
影响因子：
6.7
作者：
Cowen LE
通讯作者：
Cowen LE
影响因子：
2.6
作者：
Ahmad, Ausaf;Kabir, M. Anaul;Rustchenko, Elena
通讯作者：
Rustchenko, Elena
影响因子：
4.9
作者：
Yang, Feng;Zhang, Lulu;Rustchenko, Elena
通讯作者：
Rustchenko, Elena
影响因子：
3.2
作者：
RUSTCHENKOBULGAC, EP
通讯作者：
RUSTCHENKOBULGAC, EP