Polymorphism: Antifungal Drug Resistance & Adaptation in Candida

多态性：抗真菌药物耐药性

• 批准号: 9180402
• 负责人: Santosh kumar Katiyar
• 金额: $ 19.56万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180402
• 关键词: Address; Adhesions; Amino Acids; Antifungal Agents; Azole resistance; Azoles; Biological Assay; Candida; Candida albicans; Candida glabrata; Caspofungin; Cell Wall; Cell membrane; Clinical; Complement; DNA biosynthesis; Drug Efflux; Drug Targeting; Environment; Epigenetic Process; Eukaryota; Event; Fungal Drug Resistance; Fungal Proteins; Future; Genes; Genetic Polymorphism; Genomics; Haploidy; Hot Spot; Human; Huntington Disease; Immune; In Vitro; Length; Light; Mediating; Membrane; Microbial Biofilms; Mitogen-Activated Protein Kinases; Mutation; Mycoses; Neurodegenerative Disorders; Other Genetics; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma Cells; Predisposition; Proteins; Reading; Research; Resistance; Resistance development; Role; Saccharomyces cerevisiae; Set protein; Stress; Technology; Testing; Time; Tissues; Transcription Repressor/Corepressor; Yeasts; abstracting; base; chromatin modification; echinocandin resistance; fitness; fungus; gene replacement; genetic analysis; genome sequencing; in vitro Model; innovation; killings; microbial; microorganism; pathogen; polyglutamine; pressure; response; screening; transcription factor; whole genome

Project Abstract Polymeric repeats, typically consisting of only one or two different amino acids, are found within many fungal proteins, particularly those with regulatory functions. These “polyX” regions can be highly polymorphic, a consequence of slippage between repeat units during DNA replication. The general hypothesis to be tested here is that polyX polymorphisms fill the adaptation gap between conventional mutation and epigenetics. The specific focus of this R21 is the opportunistic yeast Candida glabrata, well known for its ability to develop resistance to antifungal azoles and, more recently, echinocandins. While single base mutations within C. glabrata Pdr1 or Fks proteins mediate high level resistance to these agents, there is emerging evidence that these mutations are accompanied by other genetic changes that confer reduced antifungal susceptibility or tolerance, or compensate for the decreased fitness associated with Pdr1/Fks mutation. In Aim 1, the polymorphism of 36 polyX proteins relevant to azole or echinocandin susceptibility will be assessed in 7 azole resistant and 6 echinocandin-resistant clinical isolates relative to their epidemiologically or phylogenetically matched susceptible isolates. Preliminary studies have identified one such polymorphism in the polyQ region of transcriptional repressor Tup1A that correlates with 16 to 32-fold reduced echinocandin killing. Aim 2 will directly test these correlations by using gene replacement to construct strains that differ only in the polyX content of an antifungal-relevant protein, followed by susceptibility and fitness assays. If the general hypothesis is supported, future studies would be warranted to evaluate the role of polyX polymorphism in other aspects of fungal infection, including tissue-specific adhesion, biofilm formation, and immune evasion.

项目摘要 聚合物重复序列，通常仅由一个或两个不同的氨基酸组成 真菌蛋白，特别是具有调节功能的真菌蛋白。这些“ polyx”区域可能是高度多态的， 在DNA复制过程中重复单位之间滑倒的结果。要测试的一般假设 这是多X多态性填补了常规突变和表观遗传学之间的适应差距。 R21的特定重点是机会性的酵母菌念珠菌，以其发展的能力而闻名 对抗真菌唑的抗性以及最近的echinocandins。而C中的单基突变。 glabrata pdr1或fks蛋白介导对这些药物的高水平抗性，有新兴的证据表明 这些突变是通过其他遗传变化来完成的，这些变化会降低抗真菌敏感性或 公差或补偿与PDR1/FKS突变有关的降低适应性。在AIM 1中 将在7个azole中评估与偶氮或棘齿素易感性相关的36个多X蛋白的多态性 相对于其流行病学或系统发育，耐药性和6个抗呼吸素的临床分离株 匹配的易感分离株。初步研究已经确定了Polyq区域的一种这样的多态性 转录表示tup1a与16至32倍降低的棘轮杀死相关。 AIM 2意志 直接通过使用基因替换来直接测试这些相关性，以构建仅在多克斯 抗真菌相关蛋白的含量，然后进行敏感性和适应性评估。如果是一般 支持假设，将有必要对未来的研究评估多X多态性在其他 真菌感染的各个方面，包括组织特异性粘附，生物膜形成和免疫进化。