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（由申请人证明）：白色念珠菌是从人类中分离出来的最常见的真菌病原体，是d感染的主要原因。我们的项目的目标是在高危患者中为导管的白色念珠菌生物膜形成新的策略。与哺乳动物细胞相比， - 氨基酸（称为 - 肽）可以表现出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的，而与细胞膜相关。 - 肽可以在A肽抗菌肽上拥有，包括在生理pH和毫无疑问的情况下的活性，对蛋白水解降解的耐药性稳定性。在体外和体内形成。 - 肽也折叠成两亲螺旋，并允许调节结构以外的结构 - 肽。 - 和a/¿ - 来自医疗设备表面的肽，我们将设计多层多层膜（PEM）膜，这些膜在R ATES上融合并释放与预防体内生物膜形成相关的肽。影响释放率。 - 和a/¿ - 抑制白色念珠菌生物膜的肽将通过确定与含有肽的Pemfilm的S层的生物膜形成率和结构。 - 和a/¿ - 来自PEM填充意志Will Will Wild Wifilm组成的社会念珠菌的肽低聚物。