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

基本信息

批准号：
8681304
负责人：
Sean P Palecek
金额：
$ 36.28万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/8681304
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

项目摘要

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（由申请人提供）：白色念珠菌是从人类中分离出的最常见的真菌病原体，是医院获得性感染的主要原因。系统性念珠菌血症是一种常常致命的疾病，通常与在人体表面形成的白色念珠菌生物膜有关。我们项目的目标是开发一种新策略来防止导管上白色念珠菌生物膜的形成，从而降低高危人群念珠菌血症的发生率。在之前的工作中，PI 鉴定出 ¿ 的阳离子两亲性低聚物。与哺乳动物细胞相比，β-氨基酸（称为 β-肽）可以表现出高水平的针对白色念珠菌的特异性活性。 -肽是基于与天然抗菌肽的结构相似性而设计的，当与细胞膜结合时，天然抗菌肽通常折叠成两亲性阳离子螺旋。 β-肽可被设计为具有优于α-肽抗菌肽的关键优势，包括在生理pH和离子强度下的活性、更高的结构稳定性以及对蛋白水解降解的抵抗力。在这里，我们将设计活性和选择性螺旋-肽化合物并评估其能力。此外，我们将研究混合 a/¿ 的特定抗真菌活性。 -肽，也折叠成两亲性螺旋，并允许调节超出 ¿ 的结构-肽促进抗真菌药物的传递。 - 和一个/¿ -来自医疗器械表面的肽，我们将设计聚电解质多层 (PEM) 薄膜，该薄膜以与预防导管应用中体内生物膜形成相关的速率掺入和释放肽。我们将评估薄膜厚度、薄膜交联和肽结构。和化学性质影响抗真菌的能力。 - 和一个/¿ -通过确定涂有肽的PEM膜的基底上的生物膜形成速率和生物膜结构，对抑制白色念珠菌生物膜形成的肽进行体外定量，然后使用大鼠中心静脉导管模型在体内评估优化的肽和释放策略。这些结果将共同检验 ¿ - 和一个/¿来自导管上 PEM 膜的肽寡聚物将抑制白色念珠菌生物膜的形成，并可能建立预防装置相关念珠菌血症的新范例。