New Antiobiotics Against Drug-Resistant Pathogens from Marine Natural Products

来自海洋天然产物的针对耐药病原体的新型抗生素

• 批准号: 7808178
• 负责人: Nina Marie Haste
• 金额: $ 3.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808178
• 关键词: Abscess; Actinobacteria class; Actinomyces; Address; Antibiotics; Bacteria; Bacterial DNA; Bacterial Infections; Behavioral; Biochemical; Biological Assay; Biological Factors; Body Weight; Cell Membrane Permeability; Cell Wall; Characteristics; Chemicals; Chemistry; Clinical; Collaborations; Communicable Diseases; DNA; Data; Development; Drug Kinetics; Drug Monitoring; Drug resistance; Exhibits; Exposure to; Flow Cytometry; Genetic; Goals; Hela Cells; High Pressure Liquid Chromatography; In Vitro; Infection; Institutes; Institution; Label; Laboratories; Link; Malignant Neoplasms; Marines; Mass Spectrum Analysis; Measures; Medical; Methods; Microbiology; Minimum Inhibitory Concentration measurement; Modeling; Multi-Drug Resistance; Mus; Mutagenesis; Natural Products Chemistry; Oceanography; Oceans; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacy Schools; Plasma; Prevalence; Productivity; Property; Propidium Diiodide; Protein Biosynthesis; Protocols documentation; Public Health; RNA; Radio; Radiolabeled; Research Project Grants; Resistance; Resistance development; Sampling; Serial Passage; Structure; Structure-Activity Relationship; Techniques; Testing; The Sun; Therapeutic; Therapeutic Index; Thigh structure; Time; Toxic effect; Treatment Efficacy; Work; antimicrobial; bactericide; clinical efficacy; cytotoxic; cytotoxicity; drug candidate; drug resistant microorganism; food consumption; in vitro activity; in vivo; killings; liquid chromatography mass spectrometry; marine natural product; methicillin resistant Staphylococcus aureus; mouse model; novel; pathogen; professor; protein expression; public health relevance; radiotracer; research study; scaffold

DESCRIPTION (provided by applicant): The widespread and common use of antibiotics to treat many infectious diseases has allowed for the selection and continual emergence of multiple-drug resistant pathogens. There is an urgent need for the development of novel antibiotics to target these infections. This research project will focus on finding novel therapies to treat methicillin-resistant Staphylococcus aureus (MRSA). Previous work by William Fenical and Paul Jensen at Scripps Institution of Oceanography showed deep ocean sediments contain actinomycetes that produce a rich and diverse array of natural products. Two new classes of compounds with novel structures, the marinopyrroles and napyradiomycins, have been identified from marine actinomycete bacteria. These compounds exhibit promising preliminary data, showing potent antibiotic activities against drug-resistant MRSA. The overall goal of this project is evaluate the pharmacological and therapeutic potential of these two novel classes of antibiotics in treating infections caused by drug-resistant MRSA. We will investigate and evaluate the marinopyrrole and napyradiomycin classes of compounds as detailed in three specific aims, creating interdisciplinary links between infectious disease microbiology, marine natural product chemistry and pharmacology. The first aim is to assess the antimicrobial properties of the marinopyrroles and napyradiomycins isolated from marine actinomycetes by measuring in vitro activity, capacity for resistance development, and synergistic activities with known antibiotics. The second aim is to determine the pharmacological characteristics of these novel classes of compounds by testing their in vitro bactericidal activity, post-antibiotic effect and cytotoxic effects. We will study the in vivo pharmacokinetic and pharmacodynamic profiles of the candidate antibiotics in a mouse model. The third aim is to define the mechanisms of action of the marinopyrrole and napyradiomycin classes of antibiotics by evaluating bacterial cell wall integrity and using radiolabeled precursors to measure changes in bacterial DNA, RNA and protein syntheses. We will collaborate with other laboratories to employ methods such as mass-spectrometry and structure-activity relationship studies to further understand mechanism of action. PUBLIC HEALTH RELEVANCE: The widespread emergence and increasing prevalence of infections caused by multiple drug-resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA), is a distinct medical concern. An urgent need exists for the discovery of novel antibiotics to treat these infections. The goal of this project is to discover and develop new antibiotics derived from marine- natural products to target drug-resistant MRSA and address this public health crisis.

描述（由申请人提供）：抗生素的广泛和常见用途可以治疗许多传染病，可以选择和持续出现多药耐药病原体。迫切需要开发新型抗生素来靶向这些感染。该研究项目将着重于寻找新的疗法来治疗金黄色葡萄球菌（MRSA）。斯克里普斯海洋学研究所的威廉·菲尼克（William Fenical）和保罗·詹森（Paul Jensen）的先前工作表明，深海沉积物中包含产生各种天然产物的繁殖术的放线菌。已经从海洋放线菌细菌中鉴定出了两种具有新型结构的新型化合物，即海洋吡咯并萘霉素。这些化合物表现出有希望的初步数据，显示了针对耐药MRSA的有效抗生素活性。该项目的总体目标是评估这两种新型抗生素类型在治疗由耐药MRSA引起的感染中的药理和治疗潜力。我们将研究和评估三个特定目标中详细介绍的化合物的海洋吡咯和萘霉素类别，从而在传染病微生物学，海洋天然产物化学和药理学之间建立跨学科的联系。第一个目的是通过测量体外活性，耐药性发展的能力以及具有已知抗生素的协同活性来评估从海洋放线菌中分离出的海洋吡咯和萘霉菌素的抗菌特性。第二个目的是通过测试其体外杀菌活性，抗抗生素后作用和细胞毒性作用来确定这些新型化合物的药理特征。我们将研究小鼠模型中候选抗生素的体内药代动力学和药效学特征。第三个目的是通过评估细菌细胞壁完整性并使用放射性标记的前体来测量细菌DNA，RNA和蛋白质合成的变化来定义抗生素的海洋吡咯和萘霉素类别的作用机理。我们将与其他实验室合作采用诸如质谱和结构活动关系研究之类的方法，以进一步了解作用机理。 公共卫生相关性：多种耐药微生物（例如耐甲氧西林金黄色葡萄球菌（MRSA））引起的感染引起的感染的普遍出现和增加的感染率是一个明显的医学问题。迫切需要发现新型抗生素来治疗这些感染。该项目的目的是发现和开发从海洋天然产品中衍生出的新抗生素，以靶向耐药的MRSA并解决这一公共卫生危机。