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: 8078019
• 负责人: Roman Dziarski
• 金额: $ 37.73万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078019
• 关键词: Air; Amidohydrolases; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Genes; Bacterial Infections; Biological Warfare; Bioterrorism; Cell Wall; Cells; Complement; Confocal Microscopy; 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; 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）：尽管有大量有效的抗生素和现代生命支持疗法，但细菌感染仍然是发病率和死亡率的主要原因，尤其是在医院患者，老年人和免疫功能低下。此外，至少有18种细菌可用于生物恐怖袭击或生物战，并对公共卫生构成重大潜在威胁。这种攻击的暴露可能涉及受污染的空气，物体，食物或水，并且该药物最初可能不知道或可能是几种细菌的混合物。因此，在所有这些小组中，对许多细菌的直接和广泛的保护在宿主防御的早期阶段将是最有益的，以防止或阻止进入入口处（例如皮肤，眼睛，胃肠道和上呼吸道）。由于对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最初暴露后立即对抗此类细菌感染的最有效的第一道防线。因此，增强与细菌接触部位的宿主抗菌先天免疫力可以防止建立感染或补充其他疗法，并在流行病，生物战或生物恐怖主义攻击中挽救生命，或在可能引起严重感染的细菌暴露中。一组可用于预防这种感染的人类杀菌蛋白是肽聚糖识别蛋白（PGLYRPS）。由于PGLYRP自然是在人体皮肤，粘膜和汗水，皮脂和唾液中生产的，因此可以将它们发展为有效保护人们免受细菌感染的有用药物。这些研究的长期目标是开发具有较高活性和广泛活性的PGLYRP分子为临床适用的药物，可用于增强宿主防御细菌感染。该应用的目的是确定PGLYRP杀死细菌的机制。该应用的具体目的是：（a）确定PGLYRP在细菌中的形态学位点以及其杀菌活性的确切机制，包括测试通过酶水性水解机制抑制细菌细胞肽肽聚细胞或乳脂细菌中肽聚糖合成的假设； （b）定义PGLYRP的特异性及其活动的要求； （c）确定细菌是否可能对PGLYRPS抗性并鉴定负责抗性的细菌基因。该建议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到临床适用的药物中，这些蛋白质将来可以用来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抗性增加，因此需要新的抗菌剂。