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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该项目将系统地检验以下假设：通过与抗菌肽，人乳铁蛋白和/或meveol协同相互作用，可增强作用在铜绿假单胞菌生物膜上的基因工程人溶菌酶（HLYS）的抗菌特性。下呼吸道的慢性感染导致细胞外，阴离子，生物聚合物（例如DNA，F-肌动蛋白，粘蛋白）的积累，在粘液类铜绿假单胞菌感染的情况下，外多糖藻酸盐藻酸盐。这些感染气道中这些生物聚合物的高局部浓度被认为会抑制阳离子抗菌肽和蛋白质，并且在人溶菌酶（HLYS）功能方面尤其有问题。在存在临床相关的抑制性生物聚合物的情况下，我们已经成功地重新设计了Hlys的静电潜力，以产生具有增强杀菌活性的酶变体（2）。初步动物研究表明，与野生型蛋白质或PBS对照相比，至少一种增强的人类溶菌酶（EHLYS）在肺部感染的小鼠模型中减轻了铜绿假单胞菌的负担。将这项研究扩展到具有更大的临床影响，我们在这里假设该酶的抗假符活性将通过与互补抗菌肽，抗菌蛋白人类人乳酸素或meveol共同给药，从而大大改善该酶的抗星素活性。