ASSESSING SYNERGIES OF ANTIBACTERIAL PROTEINS AGAINST P AERUGINOSA BIOFILMS

评估抗菌蛋白对铜绿假单胞菌生物膜的协同作用

• 批准号: 8359709
• 负责人: Karl E Griswold
• 金额: $ 5.94万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359709
• 关键词: Alginates; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Biopolymers; Chronic; Clinical; DNA; Electrostatics; Engineering; Enzymes; F-Actin; Funding; Grant; Human; Human Engineering; Infection; Lactoferrin; Lower Respiratory Tract Infection; Lung; Lung diseases; Microbial Biofilms; Molecular; Mucins; Muramidase; National Center for Research Resources; Peptides; Principal Investigator; Property; Proteins; Pseudomonas aeruginosa; Research; Research Infrastructure; Resources; Source; Testing; United States National Institutes of Health; Variant; antimicrobial peptide; bactericide; clinically relevant; cost; enzyme activity; extracellular; improved; mouse model; mucoid

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project will systematically test the hypothesis that the antibacterial properties of genetically engineered human lysozyme (hLYS) acting on P. aeruginosa biofilms is enhanced by synergistic interactions with antimicrobial peptides, human lactoferrin, and/or Meveol. Chronic infection of the lower respiratory tract results in accumulation of extracellular, anionic, biopolymers such as DNA, F-actin, mucins, and in the case of mucoid P. aeruginosa infections, the exopolysaccharide alginate. The high local concentrations of these biopolymers in the infected airway are believed to inhibit cationic antimicrobial peptides and proteins, and are particularly problematic with respect to human lysozyme (hLYS) function. We have successfully re-engineered hLYS's electrostatic potential to produce enzyme variants with enhanced bactericidal activity in the presence of clinically relevant inhibitory biopolymers (2). Preliminary animal studies have indicated that at least one enhanced human lysozyme (EhLYS), when compared against the wild type protein or PBS controls, reduces P. aeruginosa burden in a mouse model of lung infection. Extending this research to have greater clinical impact, we hypothesize here that the anti-Pseudomonal activity of this enzyme will be substantially improved by co-administration with complementary antibacterial peptides, the antibacterial protein human lactoferrin, or Meveol.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目将系统地测试基因工程人溶菌酶（hLYS）作用于铜绿假单胞菌生物膜的抗菌特性通过与抗菌肽、人乳铁蛋白和/或Meveol的协同相互作用而增强的假设。下呼吸道的慢性感染导致细胞外阴离子生物聚合物如DNA、F-肌动蛋白、粘蛋白的积累，并且在粘液样铜绿假单胞菌感染的情况下，导致胞外多糖藻酸盐的积累。这些生物聚合物在受感染的气道中的高局部浓度被认为抑制阳离子抗微生物肽和蛋白质，并且对于人溶菌酶（hLYS）功能是特别成问题的。我们已经成功地重新设计了hLYS的静电势，以在临床相关的抑制性生物聚合物的存在下产生具有增强的杀菌活性的酶变体（2）。初步的动物研究已经表明，当与野生型蛋白或PBS对照相比时，至少一种增强的人溶菌酶（EhLYS）降低了肺部感染小鼠模型中的铜绿假单胞菌负荷。将这项研究扩展到具有更大的临床影响，我们在这里假设，这种酶的抗假单胞菌活性将通过与互补抗菌肽、抗菌蛋白人乳铁蛋白或Meveol共同给药而得到实质性改善。