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
• 负责人: Sean P Palecek
• 金额: $ 34.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484784
• 关键词: Adopted; Adverse effects; Amino Acids; Antibiotic Resistance; Antifungal Agents; Biological; Biological Assay; Biological Process; Candida albicans; Catheters; Cells; Cellular Membrane; Cellular Stress; Charge; Clinical Trials; Data; Development; Devices; Diffusion; Disease; Disseminated candidiasis; Drug resistance; Drug usage; Exhibits; Film; Goals; Growth; Host Defense; Human; Hydrophobicity; Implant; In Vitro; Incidence; Infection; Ionic Strengths; Length; Mammalian Cell; Measures; Medical; Medical Device; Methods; Microbial Biofilms; Modeling; Molecular Conformation; Monitor; Nosocomial Infections; Outcome; Patients; Peptides; Performance; Perfusion; Physiological; Plague; Prevention; Prevention approach; Procedures; Property; Rattus; Regulation; Research; Resistance; Role; Route; Safety; Side; Site; Specificity; Structure; Surface; Testing; Thick; Time; Tissues; Variant; Venous; Vertebral column; Work; antimicrobial peptide; base; biological adaptation to stress; candidemia; chemical property; controlled release; cost; crosslink; design; flexibility; high risk; improved; in vivo; insight; mortality; natural antimicrobial; novel; novel strategies; pathogen; peptide structure; prevent; research study; segregation; surface coating; uptake

DESCRIPTION (provided by applicant): Candida albicans is the most common fungal pathogen isolated from humans and is a leading cause of hospital-acquired infections. Systemic candidemia, an often fatal disease, is typically associated with C. albicans biofilms formed on the surface of indwelling medical devices. The goal of our project is to develop a novel strategy to prevent C. albicans biofilm formation on catheters, and to thereby reduce the incidence of candidemia in high-risk patients. In prior work the PI identified that cationic, amphiphilic oligomers of ¿-amino acids (called ¿-peptides) can exhibit high levels of specific activity against C. albicans as compared to mammalian cells. These ¿-peptides were designed based on structural similarity to natural antimicrobial peptides, which typically fold into amphiphilic cationic helices when associated with cellular membranes. However, ¿-peptides can be designed to possess key advantages over a-peptide antimicrobial peptides including activity at physiologic pH and ionic strength, greater structural stability, and resistance to proteolytic degradation. Here, we will design active and selective helical -peptides compounds and assess their ability to prevent C. albicans biofilm formation in vitro and in vivo. Additionally, we will investigate the specific antifungal activity of mixed a/¿-peptides, which also fold into amphiphilic helices, and permit regulation of structure beyond that of ¿-peptides. To facilitate delivery of antifungal ¿- and a/¿-peptides from the surface of medical devices we will design polyelectrolyte multilayer (PEM) films that incorporate and release the peptides at rates relevant for prevention of biofilm formation in vivo in catheter applications. We will assess how film thickness, film crosslinking, and peptide structures and chemical properties influence rate of release. The ability of antifungal ¿- and a/¿-peptides to inhibit C. albicans biofilm formation will be quantified in vitro by determining biofilm formation rate and biofilm structure on substrates coated with peptide-incorporated PEM films. Optimized peptides and release strategies will then be assessed in vivo using a rat central venous catheter model. Together these results will test the prediction that delivery of ¿- and a/¿-peptide oligomers from a PEM film on a catheter will inhibit C. albicans biofilm formation, and may establish a new paradigm for prevention of device-associated candidemia.

描述（由适用提供）：白色念珠菌是从人类分离的最常见的真菌病原体，是医院获得感染的主要原因。全身性念珠菌血症通常是一种致命的疾病，通常与在留置医疗设备表面形成的白色念珠菌生物膜有关。我们项目的目的是制定一种新的策略，以防止白色念珠菌生物膜在导管上形成，从而减少高危患者中念珠菌的事件。在先前的工作中，PI确定与哺乳动物细胞相比，对氨基酸的阳离子，两亲性寡聚物（称为�-肽）可以表现出高水平的特异性活性。这些 - 肽是基于与天然抗菌胡椒体的结构相似性设计的，当与细胞膜相关时，通常会折叠成两亲性阳离子螺旋。然而，可以设计肽比A肽抗菌胡椒具有关键优势，包括生理pH值和离子强度的活性，更大的结构稳定性以及对蛋白水解降解的耐药性。在这里，我们将设计活性和选择性的螺旋肽化合物，并评估它们在体外和体内预防白色念珠菌生物膜形成的能力。此外，我们将研究混合A/肽的特异性抗真菌活性，该肽也折叠成两亲性螺旋，并允许调节结构以外的结构。为了从医疗设备的表面产生抗真菌�-和A/�-肽，我们将设计聚电解质多层膜（PEM）膜，该膜以与预防在导管应用中体内生物膜形成相关的速度和释放Petides。我们将评估膜的厚度，膜交联以及肽结构以及化学性质如何影响释放速率。通过确定涂有肽含有PEM膜的肽的底物上的生物膜形成速率和生物膜结构，将在体外量化抗真菌�-肽和肽抑制白色念珠菌生物膜形成的能力。然后，将使用大鼠中央静脉导管模型在体内评估优化的肽和释放策略。这些结果将共同测试以下预测：从导管上的PEM膜中递送 - 和A/¿ - 肽寡聚物将抑制白色念珠菌生物膜的形成，并可能建立一个新的范式，以预防设备相关的候选血症。