Universal Anti-PAMP Agent to Improve Wound Healing

促进伤口愈合的通用抗 PAMP 剂

• 批准号: 10527023
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527023
• 关键词: Acetylmuramyl-Alanyl-Isoglutamine; Affinity; Anti-Inflammatory Agents; Antibiotic Resistance; Bacteremia; Bacteria; Binding; Binding Proteins; Binding Sites; Biochemical; CD14 gene; Calorimetry; Cations; Cells; Cessation of life; Chemicals; Chronic; 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; Lead; Libraries; Link; Lipopolysaccharides; 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; Peptidoglycan; Persons; Pharmaceutical Preparations; Phase; Play; Proteins; Proteolysis; Pseudomonas aeruginosa; Receptor Activation; Research; Rice; Risk; 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; macrophage; 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个体。 在这方面，病原体被“视为”对宿主危险并引发炎症反应。 能够消灭微生物，这种免疫辨别是通过识别微生物来实现的。 宿主上 Toll 样受体的特定分子（例如脂多糖、脂磷壁酸和肽聚糖） 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) 分子通过延长伤口来阻碍伤口愈合。 愈合的炎症阶段并促进慢性伤口的发展。 触发炎症细胞因子的释放将恢复最佳的炎症反应。 成功的药物难以捉摸，因为 PAMP 源自许多不同的革兰氏阴性菌和革兰氏阴性菌。 因此，需要一种针对 LPS、LTA 和 阳性细菌的通用广谱治疗剂。 PGN 细菌 PAMP。 该项目的目的是研究 PEG-BPEI 结构-活性关系。 假设增加 PEG-BPEI 的空间体积会降低其与金黄色葡萄球菌 PAMP 结合的能力， 铜绿假单胞菌、大肠杆菌和肺炎克雷伯菌因此无法干扰 PRR 的 PAMP 识别。 将通过以下具体目标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 组合如何减少 PRR 激活数据。 这些目标意义重大，因为它们有望为持续的研究提供强有力的科学依据。 该项目增加了适用于急性和慢性伤口的抗炎剂的开发。 意义重大，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；一种能够进行其他后续研究和思考的策略。 工作具有创新性，因为我们用多用途药物填补了技术空白，这些药物可以禁用 PAMP、溶解 生物膜，并克服抗生素耐药机制，使其优于现有技术。 理由是该药剂可通过抵消 LPS、LTA 和 PGN 细菌产物来改善伤口愈合 确定抑制炎症细胞因子释放的能力对于评估是必要的。 我们设想我们的发现可以作为局部药物的应用。 对于急性和慢性伤口，因为除了防止细胞因子释放的试剂的活性部分之外， 它还会破坏抗生素耐药机制并破坏生物膜基质。 表明它可能是一种理想的治疗剂，可用于数亿非慢性皮肤或软组织疾病。 每年发生 450 万起慢性伤口感染。