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Polymorphism: Antifungal Drug Resistance & Adaptation in Candida

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:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-06-01 至 2018-05-31

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中文摘要
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英文摘要
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.
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Polymorphism: Antifungal Drug Resistance & Adaptation in Candida
  • 批准号:
    9280792
  • 项目类别:
  • 资助金额:
    $19.56万
  • 财政年份:
    2016
  • 负责人:
    Santosh kumar Katiyar
  • 依托单位:
Echinocandin Reduced/Increased Susceptibility: Mechanism
  • 批准号:
    8707692
  • 项目类别:
  • 资助金额:
    $32.68万
  • 财政年份:
    2013
  • 负责人:
    Santosh kumar Katiyar
  • 依托单位:
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