Prevention of Candida biofilms by localized delivery of aurein analogues

通过局部递送金黄色素类似物预防念珠菌生物膜

基本信息

  • 批准号:
    9221080
  • 负责人:
  • 金额:
    $ 21.04万
  • 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
  • 起止时间:
    2016-12-01 至 2018-11-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Candida spp. are the most common fungal pathogens isolated from humans and are leading causes of hospital-acquired infections, largely due to colonization of indwelling medical devices including catheters. Current strategies to prevent Candida spp. infections associated with medical devices include systemic antifungals, but these drugs suffer from severe toxicity and side effects, and drug-resistant strains have emerged. The goal of our project is to develop a novel strategy to prevent C. albicans biofilm formation on catheters by designing a new antifungal drug structurally templated on the natural broad-spectrum antimicrobial peptide (AMP) aurein 1.2. Like many AMPs, aurein 1.2 adopts a helical structure and selectively permeabilizes microbial membranes via cationic and hydrophobic interactions. However, efforts to develop AMPs into drugs have been largely unsuccessful since these compounds possess low stability in physiologic environments. Here, we propose to synthesize α/β-peptide aurein 1.2 mimetics which exhibit folding patterns that present side chains in virtually identical manner to native AMPs, and thus allow the use of α/β-peptide analogues templated on native antimicrobial peptide sequences as lead compounds. α/β-peptides are much more structurally stable than native antimicrobial peptides and are resistant to proteolytic degradation, offering significant advantages for drug development. Furthermore, we propose to develop a strategy to release this drug from catheter surfaces, localizing the treatment to inhibit biofilm formation. In prior work the PI identified that cationic, amphiphilic oligomers of β-amino acids (called β-peptides) can exhibit high levels of specific activity against C. albicans as compared to mammalian cells, although efforts reached a limit of potency and specificity. Collaborations with co-investigators on this project demonstrated sustained release from catheter surfaces and inhibition of biofilm formation in vitro and in vivo. Here, we will extend our findings and approach to α/β-peptides which are composed of both α− and β-amino acids. In the first two years of this project (R21 phase) we will generate α/β-aurein analogues and determine how varying hydrophobicity, net charge, and helical stability affect activity against drug-resistant C. albicans and specificity for C. albicans vs. mammalian cells. Then we will assess whether release of these compounds from polyelectrolyte multilayer (PEM) polymer films on a catheter surface inhibits C. albicans biofilm formation in vitro and in vivo. The remainder of the project (R33 phase) will further vary α- and β-amino acid sequence and combine features of α/β-aurein analogues identified to affect activity and specificity in C. albicans to optimize broad-spectrum antifungal activity and specificity in additional pathogenic Candida spp. Finally, we will develop polymer film-mediated release of the α/β-aurein analogues for sustained inhibition of Candida spp. biofilms in an in vitro model and then evaluate effectiveness of biofilm prevention in a rat model of central venous catheter infections. Together, these results will develop a novel strategy for prevention of device-associated candidemia.
摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Sean P Palecek其他文献

Sean P Palecek的其他文献

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{{ truncateString('Sean P Palecek', 18)}}的其他基金

Label-free single-cell imaging for quality control of cardiomyocyte biomanufacturing
用于心肌细胞生物制造质量控制的无标记单细胞成像
  • 批准号:
    10675976
  • 财政年份:
    2023
  • 资助金额:
    $ 21.04万
  • 项目类别:
A Multi-Omics Approach to Discover Metabolic Critical Quality Attributes for Cardiomyocyte Biomanufacturing
发现心肌细胞生物制造代谢关键质量属性的多组学方法
  • 批准号:
    10435467
  • 财政年份:
    2019
  • 资助金额:
    $ 21.04万
  • 项目类别:
Mechanisms of Shear Induction of Blood-Brain Barrier Phenotypes in Human iPSC-derived Brain Endothelial Progenitors
人 iPSC 来源的脑内皮祖细胞血脑屏障表型的剪切诱导机制
  • 批准号:
    10328223
  • 财政年份:
    2019
  • 资助金额:
    $ 21.04万
  • 项目类别:
Mechanisms of Shear Induction of Blood-Brain Barrier Phenotypes in Human iPSC-derived Brain Endothelial Progenitors
人 iPSC 来源的脑内皮祖细胞血脑屏障表型的剪切诱导机制
  • 批准号:
    10557176
  • 财政年份:
    2019
  • 资助金额:
    $ 21.04万
  • 项目类别:
A Multi-Omics Approach to Discover Metabolic Critical Quality Attributes for Cardiomyocyte Biomanufacturing
发现心肌细胞生物制造代谢关键质量属性的多组学方法
  • 批准号:
    10218267
  • 财政年份:
    2019
  • 资助金额:
    $ 21.04万
  • 项目类别:
Prevention of Candida biofilms by localized delivery of aurein analogues
通过局部递送金黄色素类似物预防念珠菌生物膜
  • 批准号:
    9813824
  • 财政年份:
    2016
  • 资助金额:
    $ 21.04万
  • 项目类别:
Shear regulated differentiation of hPSCs to brain endothelial cells
hPSC 向脑内皮细胞的剪切调节分化
  • 批准号:
    8619338
  • 财政年份:
    2013
  • 资助金额:
    $ 21.04万
  • 项目类别:
Shear regulated differentiation of hPSCs to brain endothelial cells
hPSC 向脑内皮细胞的剪切调节分化
  • 批准号:
    8723321
  • 财政年份:
    2013
  • 资助金额:
    $ 21.04万
  • 项目类别:
Prevention of C. Albicans Biofilms by Beta-Peptide Release From Thin Films
通过薄膜释放 β 肽来预防白色念珠菌生物膜
  • 批准号:
    8681304
  • 财政年份:
    2011
  • 资助金额:
    $ 21.04万
  • 项目类别:
Prevention of C. Albicans Biofilms by Beta-Peptide Release From Thin Films
通过薄膜释放 β 肽来预防白色念珠菌生物膜
  • 批准号:
    8484784
  • 财政年份:
    2011
  • 资助金额:
    $ 21.04万
  • 项目类别:

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