Mechanism of antibacterial activity of peptidoglycan recognition proteins

肽聚糖识别蛋白的抗菌活性机制

• 批准号: 7894595
• 负责人: Roman Dziarski
• 金额: $ 38.12万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-29 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894595
• 关键词: Air; Amidohydrolases; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Genes; Bacterial Infections; Biological Warfare; Bioterrorism; Cell Wall; Cells; Complement; Cytolysis; Data; Divalent Cations; Electron Microscopy; Enzymes; Epidemic; Eukaryota; Evolution; Exposure to; Eye; Family; Food; Future; Gastrointestinal tract structure; Genetic; Goals; Gram-Negative Bacteria; Hospitals; Host Defense; Human; Hydrolysis; Immune response; Immune system; Immunocompromised Host; Infection; Inflammation Mediators; Knowledge; Life; Lytic; Membrane; Morbidity - disease rate; Mucous Membrane; Natural Immunity; Pattern; Pattern Recognition; Pattern recognition receptor; Peptides; Peptidoglycan; Phagocytosis; Prevention; Proteins; Public Health; Recombinants; Resistance; Saliva; Sebum; Series; Serum; Site; Skin; Specificity; Staging; Structure; Sweat; Sweating; Testing; Upper respiratory tract; Water; amidase; antimicrobial; antimicrobial peptide; bacterial resistance; bactericide; base; combat; design; dimer; glycosylation; killings; microorganism; mortality; mutant; older patient; peptidoglycan recognition protein; prevent

DESCRIPTION (provided by applicant): Despite the availability of numerous potent antibiotics and modern life-support therapies, bacterial infections are still a major cause of morbidity and mortality, especially in hospital patients, elderly, and immunocompromised. Moreover, at least 18 bacteria could be used in bioterrorism attack or biological warfare and pose a significant potential threat to public health. The exposure from such an attack may involve contaminated air, objects, food, or water, and the agent may not be initially known or may be a mixture of several bacteria. Therefore, in all these groups an immediate and broad-based protection against many bacteria would be most beneficial in early stages of host defense to prevent or stop the infection at the portal of entry (such as skin, eyes, gastrointestinal tract, and upper respiratory tract). Because of broad specificity of innate immunity for many bacteria, innate immunity is likely to be the most effective first line of defense to combat such bacterial infections immediately after the initial exposure. Thus, enhancing host antibacterial innate immunity at the site of contact with bacteria could prevent establishment of infection or complement other therapies, and save lives in epidemics, biological warfare or bioterrorism attacks, or in other exposures to bacteria that are likely to cause serious infections. One group of human bactericidal proteins that could be used for prevention of such infections is peptidoglycan recognition proteins (PGLYRPs). Because PGLYRPs are naturally produced on human skin, on mucous membranes, and in the sweat, sebum, and saliva, they can be developed into useful agents that can effectively protect people from infections with bacteria. The long-term goal of these studies will be to develop PGLYRP molecules with high and broad spectrum of activity into clinically applicable agents that can be used to enhance host defenses against bacterial infections. The goal of this application is to determine the mechanism through which PGLYRPs kill bacteria. The specific aims of this application are: (a) to determine the morphologic site of action of PGLYRPs in bacteria and exact mechanism of their bactericidal activity, including testing the hypotheses that they inhibit peptidoglycan synthesis in the bacterial cell wall or lyse bacteria by an enzymatic hydrolytic mechanism; (b) to define the specificities of PGLYRPs and requirements for their activity; and (c) to determine whether bacteria may become resistant to PGLYRPs and to identify bacterial genes responsible for resistance. This proposal will determine how human antibacterial proteins, called peptidoglycan recognition proteins, kill bacteria. This knowledge will help to develop these proteins into clinically applicable agents that in the future can be used to enhance people's defenses against bacterial infections. New antibacterial agents are needed because of the increasing resistance of bacteria to commonly used antibiotics.

描述（由申请人提供）：尽管有多种有效的抗生素和现代生命支持疗法，细菌感染仍然是发病和死亡的主要原因，特别是在医院患者、老年人和免疫功能低下的患者中。此外，至少有18种细菌可用于生物恐怖袭击或生物战，对公众健康构成重大潜在威胁。此类攻击的暴露可能涉及受污染的空气、物体、食物或水，并且该病原体最初可能并不为人所知，也可能是多种细菌的混合物。因此，在所有这些群体中，针对许多细菌的立即和广泛的保护在宿主防御的早期阶段是最有益的，以预防或阻止入口（例如皮肤、眼睛、胃肠道和上呼吸道）的感染。道）。由于许多细菌的先天免疫具有广泛的特异性，因此先天免疫可能是在初次接触后立即对抗此类细菌感染的最有效的第一道防线。因此，增强宿主与细菌接触部位的抗菌先天免疫可以防止感染的发生或补充其他疗法，并在流行病、生物战或生物恐怖袭击或其他可能引起严重感染的细菌暴露中挽救生命。一组可用于预防此类感染的人类杀菌蛋白是肽聚糖识别蛋白（PGLYRP）。由于PGLYRP是在人体皮肤、粘膜、汗液、皮脂和唾液中自然产生的，因此它们可以被开发成有用的制剂，可以有效地保护人们免受细菌感染。这些研究的长期目标是将具有高广谱活性的 PGLYRP 分子开发成临床适用的药物，可用于增强宿主对细菌感染的防御能力。本应用的目标是确定 PGLYRP 杀死细菌的机制。本申请的具体目的是：(a) 确定 PGLYRP 在细菌中的形态作用位点及其杀菌活性的确切机制，包括测试它们抑制细菌细胞壁中肽聚糖合成或通过酶促裂解细菌的假设。水解机理； (b) 定义 PGLYRP 的特殊性及其活动的要求； (c) 确定细菌是否可能对 PGLYRP 产生抗药性，并鉴定导致抗药性的细菌基因。该提案将确定人类抗菌蛋白（称为肽聚糖识别蛋白）如何杀死细菌。这些知识将有助于将这些蛋白质开发成临床适用的药物，未来可用于增强人们对细菌感染的防御能力。由于细菌对常用抗生素的耐药性不断增强，因此需要新的抗菌剂。