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: 10174939
• 负责人: Lynette S Cegelski
• 金额: $ 33.37万
• 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/10174939
• 关键词: AIDS/HIV problem; 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; Cause of Death; Cell Wall; Cells; Cessation of life; Chemicals; Chronic; Chronic Obstructive Airway 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; Individual; Infection; Investigation; Klebsiella pneumoniae; Label; Link; Lipids; Maps; Measurement; Measures; Membrane; Microbial Biofilms; Molecular; 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; Resort; 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/antagonist; innovation; insight; 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.

项目概要 对几乎所有抗生素的耐药性的出现凸显了引入新抗生素的迫切需要 治疗并了解抗生素的作用方式，以帮助指导新抗菌药物的开发 对耐药微生物有效。金黄色葡萄球菌与肠杆菌属、克雷伯氏菌属 肺炎杆菌、鲍曼不动杆菌、铜绿假单胞菌和屎肠球菌等分类 作为 ESKAPE 病原体，是全世界医院获得性感染的主要原因。之中 这些，耐甲氧西林金黄色葡萄球菌是抗生素耐药性死亡的主要原因 美国的感染情况。此外，这些病原体形成生物膜和持续细胞的倾向 与导致肺炎、心内膜炎、菌血症和败血症的反复和慢性感染有关。 生物膜由生长缓慢的细菌细胞组成，周围有保护性细胞外基质，而持久性 细胞是休眠的、高度耐抗生素的细菌，可以在宿主体内持续存在。在世界范围内，结核病是 仅次于艾滋病毒/艾滋病的第二大常见死因，由分枝杆菌引起 结核。在美国，非结核分枝杆菌 (NTM) 引起的呼吸道感染正在增加， 在 CF 患者和患有慢性肺病的个体中尤其普遍。治疗方法为 NTM 很复杂，与结核病类似，并且需要长期的联合药物治疗，而单一疗法则需要长期的联合治疗。 与耐药性密切相关。我们启动了抗生素发现和作用方式活动 旨在为这些严重传染病开发新疗法的计划。在这个 拟议的项目中，我们利用最近成功设计的一种新的万古霉素衍生物，万古霉素-D- 八精氨酸 (V-r8) 缀合物，可根除革兰氏阳性生物膜和持续细胞并减少 体内发病机制。我们建议揭示有关 V-r8 独特作用模式的新发现，如 与现在作为最后手段的主要高价值治疗药物相比，例如奥利万星，朝向其 开发和临床潜力，并激发新型抗菌药物的产生。研究 设计整合了跨学科的化学和生化专业知识和观点；机械论的 生物化学；和固态核磁共振方法的集成来测量整个细胞的成分变化 并确定 V-r8 和可能的多个结合位点之间的距离。此外，我们还将推出 新的实验性固态核磁共振平台使我们能够评估药物在分枝杆菌中的作用模式。 该平台将广泛适用于复杂分枝杆菌细胞壁的研究，并将 此处专门针对 CPZEN-45 的活性进行研究，CPZEN-45 是一种令人兴奋的治疗候选药物 治疗结核分枝杆菌和 NTM。