Universal Anti-PAMP Agent to Improve Wound Healing

促进伤口愈合的通用抗 PAMP 剂

• 批准号: 10647897
• 负责人: Charles V Rice
• 金额: $ 7.39万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-16 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647897
• 关键词: Acetylmuramyl-Alanyl-Isoglutamine; Affinity; Anti-Inflammatory Agents; Antibiotic Resistance; Bacteremia; Bacteria; Binding; Binding Proteins; Binding Sites; Biochemical; CD14 gene; Calorimetry; Cells; Cessation of life; Chemicals; Complex; Dangerousness; Data; Development; Discrimination; Electrostatics; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Evaluation; Extracellular Matrix; Fibroblasts; Foundations; Government; Gram-Negative Bacteria; Gram-Positive Bacteria; Granulation Tissue; Health; Human; Immune; Immune response; Impaired wound healing; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Klebsiella pneumoniae; Knowledge; Libraries; Link; Lipopolysaccharides; Macrophage; Measures; Metalloproteases; Microbe; Microbial Biofilms; Mission; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Myelogenous; Natural Immunity; Nature; Nucleotides; Outcome Study; Pattern; Pattern Recognition; Pattern recognition receptor; Peptides; Peptidoglycan; Persons; Pharmaceutical Preparations; Phase; Play; Proteins; Proteolysis; Pseudomonas aeruginosa; Receptor Activation; Research; Rice; Risk Reduction; Role; Safety; Sepsis; Signal Transduction; Skin Tissue; Soft Tissue Infections; Specificity; Speed; Staphylococcus aureus; Structure-Activity Relationship; Technology; Testing; Therapeutic; Therapeutic Agents; Thinking; Tissues; Titrations; Toll-like receptors; Topical agent; Toxic effect; United States National Institutes of Health; Vertebral column; Virulence; Virulence Factors; Work; Wound Infection; Wound models; acute wound; chronic wound; combat; community setting; cytokine; disability; healing; health care settings; improved; in vivo; innovation; keratinocyte; lipopolysaccharide-binding protein; lipoteichoic acid; migration; mortality; necrotic tissue; novel; novel strategies; pathogen; pathogenic bacteria; peptidomimetics; phosphodiester; prevent; receptor; recurrent infection; resistance mechanism; response; transcription factor; wound; wound healing

Innate immunity has considerable specificity and can discriminate between individual species of microbes. In this regard, pathogens are “seen” as dangerous to the host and elicit an inflammatory response capable of destroying the microbes. This immune discrimination is achieved through the recognition of microbe- specific molecules (e.g., lipopolysaccharide, lipoteichoic acid, and peptidoglycan) by toll-like receptors on host cells. Lipopolysaccharide, lipoteichoic acid, and peptidoglycan arising from dangerous bacteria are known as Pathogen-Associated Molecular Pattern (PAMP) molecules. PAMPs impede wound healing by lengthening the inflammatory phase of healing and contributing to the development of chronic wounds. Preventing PAMPs from triggering the release of inflammatory cytokines will restore the optimal inflammatory response. However, successful drugs are elusive because PAMPs originate from many different species of Gram-negative and Gram- positive bacteria. Therefore, the need exists for a universal broad-spectrum therapeutic against LPS, LTA, and PGN bacterial PAMPs. The objective of this project is to investigate PEG-BPEI structure-activity relationships. The central hypothesis is that increasing the steric bulk of PEG-BPEI reduces its ability to bind with PAMPs from S. aureus, P. aeruginosa, E. coli, and K. pneumoniae and thus is unable to interfere with PAMP recognition by PRRs. We will test our central hypothesis with the following specific aims: Aim 1: Correlate PEG-BPEI steric effects with PAMP binding; Aim 2: Discover how PAMP + PEG-BPEI combinations reduce PRR activation. Data arising from these aims will be significant because they are expected to provide strong scientific justification for the continued development of anti-inflammatory agents applied to acute and chronic wounds. This project has added significance because the data will be used to evaluate the strategy of using this agent to bind bacterial PAMPs and prevent cytokine release; a strategy that enables other subsequent research and thinking. The proposed work is innovative because we fill the technological gap with multi-purpose agents that disable PAMPs, dissolve biofilms, and overcome antibiotic resistance mechanisms, making them superior to existing technology. The rationale is that the agent will improve wound healing by counteracting LPS, LTA, and PGN bacterial products that cause inflammation. Determining the ability to inhibit inflammatory cytokine release is necessary to evaluate the therapeutic opportunities of the chemical molecules. We envision our discoveries as topical agents applied to acute and chronic wounds because, in addition to the active moiety of the agent preventing cytokine release, it also disables antibiotic resistance mechanisms and disrupts the biofilm matrix. This versatility of this agent suggests that it may be an ideal therapeutic agent for use in the hundreds of millions of non-chronic skin or soft- tissue infections (SSTIs), and the 4.5 million chronic wound infections, that occur each year.

先天免疫具有相当大的特异性，可以区分不同物种的 微生物。在这一点上，病原体被认为对宿主是危险的，并引发炎症反应。 能够摧毁微生物。这种免疫辨别是通过识别微生物- 宿主上Toll样受体的特异性分子(如脂多糖、脂磷壁酸和肽聚糖) 细胞。由危险细菌产生的脂多糖、脂磷壁酸和肽聚糖被称为 病原体相关分子模式(PAMP)分子。PAMPS通过延长伤口的长度来阻碍伤口的愈合 炎症阶段的愈合和促进慢性伤口的发展。防止PAMP 触发炎症细胞因子的释放将恢复最佳的炎症反应。然而， 成功的药物是难以捉摸的，因为PAMP来自许多不同的革兰氏阴性菌和革兰氏阴性菌 阳性细菌。因此，需要一种通用的广谱疗法来对抗内毒素、LTA和 PGN细菌PAMPs。 本项目的目的是研究聚乙二醇-BPEI的构效关系。中环 假说是，增加聚乙二醇-BPEI的立体体积会降低其与金黄色葡萄球菌PAMP的结合能力， 铜绿假单胞菌、大肠杆菌和肺炎克雷伯菌，因此不能干扰PRR对PAMP的识别。我们 我将通过以下具体目标来检验我们的中心假设：目标1：将PEG-BPEI空间效应与 PAMP结合；目标2：发现PAMP+PEG-BPEI组合如何降低PRR的激活。数据来源于 这些目标将是重要的，因为它们预计将为继续 急慢性创面应用抗炎药的研究进展。此项目已添加 因为这些数据将被用来评估使用这种试剂结合细菌PAMPs的策略 并防止细胞因子的释放；这是一种使其他后续研究和思考成为可能的策略。建议数 我们的工作是创新的，因为我们用多用途试剂填补了技术空白，这些试剂可以禁用PAMP，溶解 生物被膜，并克服抗生素耐药机制，使其优于现有技术。这个 基本原理是，该制剂将通过对抗内毒素、LTA和PGN细菌产物来促进伤口愈合 会引起炎症。确定抑制炎症细胞因子释放的能力对于评估是必要的 化学分子的治疗机会。我们设想我们的发现将作为局部药物应用。 对于急性和慢性伤口，因为除了有效的部分阻止细胞因子的释放外， 它还使抗生素耐药性机制失效，并扰乱生物膜基质。这种多才多艺的代理 提示它可能是一种理想的治疗剂，适用于数亿非慢性皮肤或软组织- 组织感染(SSTI)，以及每年发生的450万慢性伤口感染。