Targeting Bacterial Signaling Cascades as a Novel Antibiotic Strategy

针对细菌信号级联作为一种新型抗生素策略

• 批准号: 10509391
• 负责人: Nathan J Wlodarchak
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10509391
• 关键词: Actinobacteria class; Affect; American; Antibiotic Resistance; Antibiotics; Area; Award; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Biochemical; Biological; Cell Wall; Cells; Chemicals; Clinical; Clinical Treatment; Complement; Data; Developing Countries; Development; Disease; Drug Design; Drug Targeting; FLT3 gene; Family; Firmicutes; Future; Genetic; Genus Mycobacterium; Goals; Growth; Health; Healthcare; Healthcare Systems; Home; Homeostasis; Hospitalization; Hospitals; Human; India; Infection; Knock-out; Lead; Mediating; Membrane; Mentors; Metabolism; Middle East; Military Personnel; Multi-Drug Resistance; Mycobacterium Infections; Mycobacterium tuberculosis; Nocardia; Nosocomial pneumonia; Occupational Exposure; Organism; Outcome; Pathway interactions; Patients; Penicillins; Persons; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Predisposition; Process; Protein Kinase; Protein phosphatase; Proteins; Proteomics; Public Health; Quality of life; Research; Research Personnel; Research Priority; Resistance; Resistance development; Resources; Scientist; Series; Serine; Serine/Threonine Phosphorylation; Signal Transduction; Southeastern Asia; Staphylococcus aureus; Staphylococcus aureus infection; Stress; Structure; Structure-Activity Relationship; System; Techniques; Testing; Threonine; Time; Toxic effect; Training; Treatment Failure; Tuberculosis; United States National Institutes of Health; Vancomycin Resistance; Veterans; Veterans Health Administration; Virulence; Work; antibiotic resistant infections; beta-Lactam Resistance; beta-Lactams; burden of illness; career; cell growth; cellular transduction; clinical development; clinically relevant; combat; cost; design; drug action; drug development; drug discovery; environmental change; improved; in vivo; inhibitor; insight; kinase inhibitor; methicillin resistant Staphylococcus aureus; new therapeutic target; novel; novel drug class; novel strategies; novel therapeutics; pathogen; pharmacologic; phosphatase inhibitor; phosphoproteomics; programs; protein expression; rational design; resistance factors; resistance mechanism; resistant strain; response; skills; synergism; trait; transcriptome sequencing; transcriptomics; translational scientist

Background and Veteran significance: Pathogens such as mycobacteria and Staphylococcus aureus, are not only intrinsically antibiotic resistant, but are rapidly acquiring multi-drug resistant traits. Two billion people are currently infected with Mycobacterium tuberculosis, and an increasing proportion are resistant to clinical treatments. Methicillin resistant Staphylococcus aureus (MRSA) is a massive burden in healthcare, and vancomycin resistant strains are increasingly problematic. These resistant infections are endemic to developing countries and areas with a regular military presence, causing an increased burden for the Veterans Administration healthcare system. Furthermore, MRSA infections are a major concern in VA hospitals and are a significant cost in time, resources, and lives. New effective antibiotics are needed, and development against novel targets is needed to treat infections caused by these resistant organisms. Novel antibiotic targets: Protein kinases and phosphatases are critical in transducing cellular and environmental signals to trigger growth and division or to respond to stress and environmental changes. Human phosphorylation signaling is well studied, but bacterial signaling is less known and no antibiotics targeting these pathways exist. Penicillin-binding And Serine/Threonine Associated (PASTA) kinases are unique transmembrane kinases present in Actinobacteria and Firmicutes. PASTA kinases are necessary for virulence, making them attractive drug targets. Genetic knockouts in MRSA and pharmacological inhibition in MRSA or tuberculosis increase β-lactam susceptibility. Furthermore, genetic deletion of the cognate S/T phosphatase in MRSA increases this synergy and decreases in vivo virulence. Inhibiting both kinases and phosphatases to enhance β-lactam synergy is a novel approach to antibiotic development. Goals of this award: The goals of this award are to 1) provide time and resources to facilitate Dr. Wlodarchak’s transition from a mentored scientist to an independent translational investigator in the VA system and to 2) develop lead compounds against novel antibiotic targets in MRSA and tuberculosis. The central hypothesis tested here is that a coordinated attack on several nodes of the serine/threonine phosphorylation signaling cascade will be an effective pharmacological strategy with low likelihood of resistance development. This hypothesis will be tested by characterizing hits from a biochemical phosphatase screen, developing MRSA kinase inhibitors, and performing the first global transcriptomic and phosphoproteomic screen on MRSA under pharmacologic stress on this pathway. Expected outcomes and impacts: Upon completion of this award, it is expected that Dr. Wlodarchak will transition to a fully independent VA investigator with several well-characterized lead compounds against MRSA and tuberculosis and leads on other potential targets in this pathway. This research will provide preliminary data for a competitive VA Merit award for a translational drug development project. This will have a positive impact on not only Dr. Wlodarchak’s career but also on Veterans’ health by providing mechanistic insight on how phosphorylation signaling controls virulence and by providing tangible compounds that may become clinical drugs. This will help provide options to stifle the current antibiotic resistance crisis and thus improve patient survival and quality of life.

背景和资深意义：病原体（例如分枝杆菌和金黄色葡萄球菌）是 不仅可以固有地抗生素耐药性，而且正在迅速获得多药的耐药性状。十亿人 目前已感染结核分枝杆菌，并且比例增加对临床有抵抗力 治疗。甲氧西林金黄色葡萄球菌（MRSA）在医疗保健中是巨大的烧伤，并且 万古霉素抗性菌株越来越有问题。这些抗性感染是内在的 发展中国家和具有常规军事存在的地区，导致退伍军人的燃烧增加 管理医疗系统。此外，MRSA感染是VA医院的主要问题 是时间，资源和生活的巨大成本。需要新的有效抗生素和开发 需要针对新的靶标，以治疗这些抗性生物引起的感染。 新型抗生素靶标：蛋白激酶和磷酸酶在转导细胞和 环境信号引发增长和分裂或应对压力和环境变化。 人类磷酸化信号传导很擅长研究，但是细菌信号传导鲜为人知，没有抗生素 存在针对这些途径。青霉素结合和丝氨酸/苏氨酸相关（面食）激酶是 独特的跨膜激酶存在于肌细菌和牢固中。面食激酶是必要的 毒力使它们成为有吸引力的药物靶标。 MRSA的遗传敲除和药理学抑制 MRSA或结核病会提高β-内酰胺的敏感性。此外，同源s/t的遗传缺失 MRSA中的磷酸酶增加了这种协同作用并降低了体内病毒。抑制激酶和 增强β-内酰胺协同作用的磷酸酶是抗生素发育的新方法。 奖项的目标：该奖项的目标是1）提供时间和资源来促进博士。 Wlodarchak从指导的科学家到VA的独立翻译调查员的过渡 系统和至2）在MRSA和结核病中开发针对新型抗生素靶标的铅化合物。这 这里测试的中央假设是对序列/苏氨酸几个节点的协调攻击 磷酸化信号传导级联将是一种有效的药物策略，其可能性很小 抵抗发展。该假设将通过表征生化的命中来检验 磷酸酶筛选，发展MRSA激酶抑制剂，并进行第一个全局转录组和 在该途径上的药物学应力下，MRSA上的磷酸蛋白质组学筛选。 预期的结果和影响：该奖项完成后，可以预期Wlodarchak博士将 过渡到完全独立的VA研究者，具有几种特征良好的铅化合物 MRSA和结核病以及该途径中的其他潜在靶标。这项研究将提供 转化药物开发项目的竞争性VA功绩奖的初步数据。这将有 不仅对Wlodarchak博士的职业，而且对退伍军人的健康有积极影响 了解磷酸化信号传导如何控制病毒并通过提供可能的化合物来控制病毒 成为临床药物。这将有助于提供扼杀当前抗生素耐药性危机的选择，从而 改善患者的生存和生活质量。