Antibacterial activity of peptidoglycan recognition proteins

肽聚糖识别蛋白的抗菌活性

• 批准号: 9000206
• 负责人: Roman Dziarski
• 金额: $ 39万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-06 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000206
• 关键词: Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacillus subtilis; Bacteria; Binding Proteins; Biochemical; Biological Assay; Cell Wall; Cessation of life; Citric Acid Cycle; Data; Development; Escherichia coli; Event; Future; Generations; Genes; Goals; Gram-Positive Bacteria; Health; Human; Hydrogen Peroxide; Immune system; Infection; Knowledge; Libraries; Membrane; Metals; Mission; Modeling; NADH; Natural Immunity; Outcome; Oxidative Stress; Prevention therapy; Production; Proteins; Public Health; Quinones; Reaction; Research; Resistance; Stress; Sulfhydryl Compounds; System; Testing; United States; United States National Institutes of Health; analog; antimicrobial; bacterial resistance; bactericide; base; biological adaptation to stress; defense response; infectious disease treatment; killings; microbiome; mimetics; mutant; novel; novel strategies; novel therapeutics; peptidoglycan recognition protein; public health relevance; response; screening; whole genome

 DESCRIPTION (provided by applicant): High resistance of bacteria to antibiotics and detrimental changes to beneficial microbiome caused by frequent use of antibiotics require development of new approaches to antibacterial therapy. One promising target for such a new approach is bacterial stress responses, whose activation by human innate immunity proteins, Peptidoglycan Recognition Proteins (PGRPs), kills bacteria. The responses evoked by PGRPs in bacteria include oxidative, thiol, and metal stress, which synergistically kill bacteria by eventual shutdown of all biosynthetic reactions. The long-term goal of this project is to attain successful targeting of bacterial stress responses in antibacterial therapy and prevention by enhancing the functions of endogenous host PGRPs or by developing PGRP analogs or mimetics. However, it is not known how PGRPs induce these stress responses, what the sequence of these responses is, which responses kill bacteria and how, and which responses defend bacteria against killing. This knowledge gap is an obstacle to successful targeting of bacterial stress responses as a new approach to antibacterial therapy. The objective of this project is to fill this knowledge gap by testing the hypothesis that the following sequence of events in bacteria is responsible for PGRP-induced killing (which is based on currently available data): PGRP binding to cell wall or outer membrane → activation of regulators of multiple stress responses → increase in Crp- and Arc-controlled TCA cycle → production of NADH in TCA cycle, increased NADH utilization, and decrease in NADH/NAD+ ratio → reduction of quinones → reduction of O2 and production of O2-, H2O2, and HO* → oxidative stress → thiol stress → metal stress → membrane depolarization → energy depletion → inhibition of biosynthesis → death. These events could be sequential or some could be parallel, which will be determined in this project. This project has three Specific Aims, which will test the predictions of each of the above events in this proposed model of PGRP killing, using Escherichia coli and Bacillus subtilis as model bacteria. Aim 1 will determine that each of these proposed events actually happens during PGRP killing of bacteria (some of these events are only predictions). Aim 2 will determine which of these events participate in PGRP-induced killing and which in bacterial defense against killing, or which are a consequence of killing. Aim 3 will determine the sequence of these events in PGRP-induced killing and which events are sequential and which parallel. The expected outcome of this project will be identification of the sequence of events responsible for PGRP-induced bacterial killing and for bacterial defense against killing, and the mechanism of their induction. The health-related significance of this research will be elucidation how human innate immunity proteins kill bacteria and a possibility of future development of new approaches to antimicrobial therapy, aimed at activating the killing systems and inhibiting the defense systems in bacteria. This approach could be effective against antibiotic-resistant bacteria, which is an urgently growing problem in the United States and worldwide.

 描述（通过应用提供）：细菌对抗生素的高耐药性以及经常使用抗生素引起的有益微生物组的有害变化需要开发新方法进行抗菌治疗。这种新方法的一个承诺目标是细菌应激反应，其人类先天免疫学蛋白，肽聚糖识别蛋白（PGRP）的激活杀死了细菌。 PGRP在细菌中引起的反应包括氧化，硫醇和金属胁迫，这些应激通过最终关闭所有生物合成反应而协同杀死细菌。该项目的长期目标是通过增强内源性宿主PGRP的功能或开发PGRP类似物或模拟物来成功靶向抗菌治疗和预防细菌应激反应。但是，尚不清楚PGRP如何诱导这些压力反应，这些反应的顺序是什么，响应杀死细菌以及如何捍卫细菌避免杀死的反应。这种知识差距是成功靶向细菌应激反应的障碍，作为一种新的抗菌治疗方法。 The objective of this project is to fill this knowledge gap by testing the hypothesis that the following sequence of events in bacteria is responsible for PGRP-induced killing (which is based on currently available data): PGRP binding to cell wall or outer membrane → activation of regulators of multiple stress responses → increase in Crp- and Arc-controlled TCA cycle → production of NADH in TCA cycle, increased NADH utilization, and decrease在NADH/NAD+比率中→喹酮的减少→O2的还原和O2-，H2O2的产生以及HO*→氧化物应力→硫醇应激→金属应力→金属应激→膜定义→能量部署→抑制生物合成→死亡。这些事件可以是顺序的，也可以是平行的，这将在此项目中确定。该项目具有三个特定的目标，该目标将使用大肠杆菌和枯草芽孢杆菌作为模型细菌来测试该提出的PGRP杀戮模型中上述每个事件的预测。 AIM 1将确定这些提出的事件中的每一个实际上发生在细菌的PGRP杀死期间（其中一些事件只是预测）。 AIM 2将确定其中哪些事件参与了PGRP引起的杀戮，哪些是针对杀害的细菌防御，或者是杀害的结果。 AIM 3将在PGRP诱导的杀戮中确定这些事件的序列，以及哪些事件是顺序的，哪些是平行的。该项目的预期结果将是确定导致PGRP引起的细菌杀死和防止杀戮的细菌防御的事件序列以及其诱导机制。这项研究的意义将是阐明人类先天免疫学蛋白如何杀死细菌，以及未来开发新的抗菌治疗方法的可能性，旨在激活杀伤系统并抑制细菌中的防御系统。这种方法可以有效地抵抗抗生素耐药细菌，这在美国和全球范围内迫切地越来越多。