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，可以区分单个物种， 微生物在这方面，病原体被“视为”对宿主有危险，并引起炎症反应 能够消灭微生物。这种免疫识别是通过识别微生物来实现的- 特定分子（例如，脂多糖、脂磷壁酸和肽聚糖）通过宿主上的Toll样受体 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 炎症阶段的愈合和促进慢性伤口的发展。防止PAMP 触发炎性细胞因子的释放将恢复最佳的炎性反应。然而，在这方面， 成功的药物是难以捉摸的，因为PAMP来源于许多不同种类的革兰氏阴性和革兰氏阴性细菌， 阳性细菌因此，需要一种针对LPS、LTA和LPS的通用广谱治疗剂。 PGN细菌PAMP。 本项目的目的是研究PEG-BPEI的结构-活性关系。中央 假设是增加PEG-BPEI的空间体积会降低其与来自S.金黄色， P. aeruginosa、铜绿假单胞菌E. coli和K.因此，PAMP不能干扰PRR对PAMP的识别。我们 将测试我们的中心假设与以下具体目标：目标1：相关的PEG-BPEI空间效应与 PAMP结合;目的2：探索PAMP + PEG-BPEI组合如何降低PRR激活。数据来源于 这些目标将是重要的，因为它们有望为继续进行科学研究提供强有力的科学依据。 开发应用于急性和慢性伤口的抗炎剂。该项目增加了 重要性，因为数据将用于评估使用该试剂结合细菌PAMP的策略 并防止细胞因子释放;这一策略使其他后续研究和思考成为可能。拟议 工作是创新的，因为我们填补了技术空白与多功能代理，禁用PAMP，溶解 生物膜，并克服抗生素耐药性机制，使其上级现有技术。的 基本原理是该试剂将通过对抗LPS、LTA和PGN细菌产物来改善伤口愈合 会引起炎症确定抑制炎性细胞因子释放的能力对于评估 化学分子的治疗机会。我们设想我们的发现作为局部药物应用于 急性和慢性伤口，因为除了防止细胞因子释放的试剂的活性部分之外， 它还使抗生素抗性机制失效并破坏生物膜基质。这种多功能性的药剂 表明它可能是用于数亿非慢性皮肤或软组织疾病的理想治疗剂， 组织感染（SSTI）和每年发生的450万慢性伤口感染。