Bacterial Cell Wall Composition and the Influence of Antibiotics

细菌细胞壁的组成和抗生素的影响

• 批准号: 10643821
• 负责人: Lynette S Cegelski
• 金额: $ 33.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10643821
• 关键词: Accounting; Acinetobacter baumannii; Address; Anabolism; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antimycobacterial Agents; Bacteremia; Bacteria; Bacterial Infections; Binding; Binding Sites; Biochemical; Biochemistry; Biology; Biophysics; Categories; Cause of Death; Cell Wall; Cells; Cessation of life; Chemicals; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Combination Drug Therapy; Communicable Diseases; Complex; Coupled; Development; Drug Design; Drug resistance; ESKAPE pathogens; Electron Microscopy; Endocarditis; Enterobacter; Enterococcus faecium; Exhibits; Extracellular Matrix; Foundations; Generations; Genus Mycobacterium; Gram-Positive Bacteria; HIV/AIDS; Individual; Infection; Investigation; Klebsiella pneumoniae; Label; Link; Lipids; Maps; Measurement; Measures; Membrane; Microbial Biofilms; Molecular; Mycobacterium Infections; Mycobacterium avium; Mycobacterium smegmatis; Mycobacterium tuberculosis; Mycolic Acid; Nosocomial Infections; Organism; Parents; Pathogenesis; Peptidoglycan; Pharmaceutical Preparations; Phase; Pneumonia; Population; Positioning Attribute; Pseudomonas aeruginosa; Research Design; Resistance; Respiratory Tract Infections; Role; S phase; Sampling; Sepsis; Signal Transduction; Staphylococcus aureus; Stress; Structure; Teichoic Acids; Testing; Therapeutic; Tuberculosis; United States; Vancomycin; antibiotic resistant infections; antibiotic tolerance; antimicrobial; arabinogalactan; chronic infection; cystic fibrosis patients; design; drug development; experimental study; improved; in vivo; inhibitor; innovation; insight; member; methicillin resistant Staphylococcus aureus; mortality; mycobacterial; non-tuberculosis mycobacteria; novel strategies; novel therapeutics; oritavancin; pathogen; preclinical development; programs; recurrent infection; solid state nuclear magnetic resonance; success; synergism; therapeutic candidate; Accounting; Acinetobacter baumannii; Address; Anabolism; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antimycobacterial Agents; Bacteremia; Bacteria; Bacterial Infections; Binding; Binding Sites; Biochemical; Biochemistry; Biology; Biophysics; Categories; Cause of Death; Cell Wall; Cells; Cessation of life; Chemicals; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Combination Drug Therapy; Communicable Diseases; Complex; Coupled; Development; Drug Design; Drug resistance; ESKAPE pathogens; Electron Microscopy; Endocarditis; Enterobacter; Enterococcus faecium; Exhibits; Extracellular Matrix; Foundations; Generations; Genus Mycobacterium; Gram-Positive Bacteria; HIV/AIDS; Individual; Infection; Investigation; Klebsiella pneumoniae; Label; Link; Lipids; Maps; Measurement; Measures; Membrane; Microbial Biofilms; Molecular; Mycobacterium Infections; Mycobacterium avium; Mycobacterium smegmatis; Mycobacterium tuberculosis; Mycolic Acid; Nosocomial Infections; Organism; Parents; Pathogenesis; Peptidoglycan; Pharmaceutical Preparations; Phase; Pneumonia; Population; Positioning Attribute; Pseudomonas aeruginosa; Research Design; Resistance; Respiratory Tract Infections; Role; S phase; Sampling; Sepsis; Signal Transduction; Staphylococcus aureus; Stress; Structure; Teichoic Acids; Testing; Therapeutic; Tuberculosis; United States; Vancomycin; antibiotic resistant infections; antibiotic tolerance; antimicrobial; arabinogalactan; chronic infection; cystic fibrosis patients; design; drug development; experimental study; improved; in vivo; inhibitor; innovation; insight; member; methicillin resistant Staphylococcus aureus; mortality; mycobacterial; non-tuberculosis mycobacteria; novel strategies; novel therapeutics; oritavancin; pathogen; preclinical development; programs; recurrent infection; solid state nuclear magnetic resonance; success; synergism; therapeutic candidate

PROJECT SUMMARY The emergence of resistance to almost every antibiotic underscores the urgent need to introduce new therapeutics and to understand antibiotic modes of action to help guide the development of new antimicrobials effective against drug-resistant organisms. S. aureus together with Enterobacter species, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecium, are categorized as the ESKAPE pathogens and are predominant causes of hospital-acquired infection worldwide. Among these, methicillin-resistant Staphylococcus aureus is the leading cause of mortality from antibiotic-resistant infections in the United States. Moreover, the propensity of these pathogens to form biofilms and persister cells is linked to recurrent and chronic infections leading to pneumonia, endocarditis, bacteremia, and sepsis. Biofilms consist of slow-growing bacterial cells surrounded by a protective extracellular matrix, while persister cells are dormant, highly antibiotic-tolerant bacteria that can persist in the host. Worldwide, tuberculosis is the second most common cause of death, following deaths from HIV/AIDS, and is caused by Mycobacterium tuberculosis. In the U.S., respiratory infections from non-tuberculosis mycobacteria (NTM) are increasing, notably prevalent among CF patients and individuals suffering from chronic lung disease. The treatment for NTM is complex, similar to that for TB, and requires prolonged combination drug therapy as monotherapy is highly associated with drug resistance. We have initiated an antibiotic discovery and mode-of-action activity program directed at the development of new therapeutics for these serious infectious diseases. In this proposed project, we leverage our recent success in designing a new vancomycin derivative, a vancomycin-D- octaarginine (V-r8) conjugate, that eradicates Gram-positive biofilm and persister cells and reduces pathogenesis in vivo. We propose to uncover new discoveries regarding V-r8’s unique mode of action, as compared to major high-value therapeutics that are now the drugs of last resort, e.g. oritavancin, towards its development and clinical potential and to inspire the generation of new antibacterial agents. The research design integrates interdisciplinary chemical and biochemical expertise and perspectives; mechanistic biochemistry; and integration of solid-state NMR approaches to measure compositional changes in whole cells and to determine distances between V-r8 and possible multiple binding sites. Furthermore, we will launch a new experimental solid-state NMR platform to enable us to evaluate drug modes of action in mycobacteria. This platform will be broadly applicable to investigations of complex mycobacterial cell walls and will be specifically directed here to interrogate the activity of CPZEN-45, an exciting therapeutic candidate for the treatment of both Mycobacterium tuberculosis and NTM.

项目摘要 几乎每种抗生素的抗药性的出现强调了迫切需要引入新的 治疗和了解抗生素的作用模式，以帮助指导新抗微生物的发展 有效抵抗耐药生物。 S.金黄色葡萄球菌与肠杆菌物种Klebsiella 肺炎，baumannii，铜绿假单胞菌和肠球菌被分类 作为Eskape病原体，是全球医院获得感染的主要原因。之中 这些，耐甲氧西林金黄色葡萄球菌是抗生素抗生素死亡率的主要原因 美国感染。此外，这些病原体形成生物膜和持久细胞的承诺 与复发性和慢性感染有关，导致肺炎，心内膜炎，细菌和败血症。 生物膜由生长慢的细菌细胞组成，这些细菌细胞被保护性细胞外基质包围，而持久性 细胞是休眠，高度抗生素的细菌，可以持续在宿主中。全球，结核病是 第二个最常见的死亡原因，继HIV/AIDS死亡之后，是由分枝杆菌引起的 结核。在美国，非连结蛋细菌（NTM）的呼吸道感染正在增加， 在CF患者和患有慢性肺部疾病的患者中，人们特别普遍。治疗 NTM很复杂，类似于TB，并且需要长时间的组合药物治疗，因为单一疗法是 与耐药性高度相关。我们已经启动了抗生素发现和行动方式 计划针对这些严重传染病的新疗法开发。在这个 拟议的项目，我们利用了我们最近在设计新的万古霉素衍生物（Vanomycin-d-）方面的成功成功 八核（V-R8）共轭物，radiomates革兰氏阳性生物膜并持久细胞并减少 体内发病机理。我们建议揭示有关V-R8独特行动方式的新发现， 与现在是Last Resort药物的主要高价值疗法相比，例如Oritavancin，朝向它 开发和临床潜力，并激发新的抗菌剂的产生。研究 设计综合的跨学科化学和生化专业知识和观点；机理 生物化学；以及固态NMR方法的整合以测量全细胞中的组成变化 并确定V-R8和可能的多个结合位点之间的距离。此外，我们将推出 新的实验固态NMR平台使我们能够评估分枝杆菌中的药物作用模式。 该平台将广泛适用于复杂的分枝杆菌墙的投资，将是 此处专门针对CPZEN-45的活动进行询问，CPZEN-45是令人兴奋的治疗候选者 治疗结核分枝杆菌和NTM。