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.

项目摘要 几乎所有抗生素都出现了耐药性，这突出表明迫切需要引入新的抗生素。 了解抗生素的作用模式，以帮助指导新抗菌药物的开发 有效对抗抗药性微生物。S.金黄色葡萄球菌与肠杆菌属、克雷伯菌 肺炎杆菌、鲍曼不动杆菌、铜绿假单胞菌和屎肠球菌 作为ESKAPE病原体，是全球医院获得性感染的主要原因。之间 耐甲氧西林金黄色葡萄球菌是耐甲氧西林金黄色葡萄球菌死亡的主要原因。 在美国感染。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、菌血症和败血症的复发性和慢性感染有关。 生物膜由生长缓慢的细菌细胞组成，细胞外基质具有保护作用， 细胞是休眠的，高度耐腐的细菌，可以在宿主中持续存在。在世界范围内，结核病是 结核分枝杆菌是继艾滋病毒/艾滋病之后的第二大常见死因，由分枝杆菌引起 结核在美国，来自非结核分枝杆菌（NTM）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。的治疗 NTM是复杂的，类似于结核病，需要长期的联合药物治疗，因为单药治疗是 与耐药性高度相关。我们已经启动了一项抗生素发现和作用模式活动 该计划旨在开发针对这些严重传染病的新疗法。在这 建议的项目，我们利用我们最近的成功，设计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，其根除革兰氏阳性生物膜和持留细胞，并减少 体内发病机制。我们建议揭示关于V-r8独特作用模式的新发现， 与目前作为最后手段的主要高价值治疗药物（如奥利万星）相比， 开发和临床潜力，并激发新的抗菌剂的产生。研究 设计整合了跨学科的化学和生物化学专业知识和观点; 生物化学;以及整合固态NMR方法来测量整个细胞中的成分变化 并确定V-r8和可能的多个结合位点之间的距离。此外，我们将推出一个 新的实验性固态NMR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， 在此专门针对询问CPZEN-45的活性，CPZEN-45是一种令人兴奋的治疗候选物， 治疗结核分枝杆菌和NTM。