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，可以区分不同的个体物种