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）：抗生素广泛且普遍地用于治疗许多传染病，导致了多重耐药病原体的选择和不断出现。迫切需要开发针对这些感染的新型抗生素。该研究项目将重点寻找治疗耐甲氧西林金黄色葡萄球菌 (MRSA) 的新疗法。斯克里普斯海洋学研究所的 William Fenical 和 Paul Jensen 之前的研究表明，深海沉积物中含有放线菌，可以产生丰富多样的天然产物。已从海洋放线菌中鉴定出两类具有新颖结构的新化合物，即马林吡咯和那吡放射霉素。这些化合物显示出有希望的初步数据，显示出针对耐药 MRSA 的有效抗生素活性。该项目的总体目标是评估这两类新型抗生素在治疗耐药 MRSA 引起的感染方面的药理学和治疗潜力。我们将按照三个具体目标详细研究和评估 marinopyrrole 和 napyradiomycin 类化合物，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联系。第一个目的是通过测量体外活性、耐药性发展能力以及与已知抗生素的协同活性，评估从海洋放线菌中分离出的马林吡咯和那吡放射霉素的抗菌特性。第二个目的是通过测试这些新型化合物的体外杀菌活性、抗生素后效应和细胞毒性效应来确定它们的药理学特征。我们将在小鼠模型中研究候选抗生素的体内药代动力学和药效学特征。第三个目标是通过评估细菌细胞壁完整性并使用放射性标记前体测量细菌 DNA、RNA 和蛋白质合成的变化来确定 marinopyrrole 和 napyradiomycin 类抗生素的作用机制。我们将与其他实验室合作，利用质谱、构效关系研究等方法来进一步了解作用机制。 公共卫生相关性：由多种耐药微生物（例如耐甲氧西林金黄色葡萄球菌 (MRSA)）引起的感染的广泛出现和患病率不断上升，是一个独特的医学问题。迫切需要发现治疗这些感染的新型抗生素。该项目的目标是发现和开发从海洋天然产品中提取的新型抗生素，以针对耐药 MRSA 并解决这一公共卫生危机。