Novel Antimalarials from Marine Microbial Natural Products

来自海洋微生物天然产物的新型抗疟药

• 批准号: 8302637
• 负责人: DEBOPAM CHAKRABARTI
• 金额: $ 22.84万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302637
• 关键词: Antimalarials; Area; Biodiversity; Biological Assay; Biological Factors; Cell Line; Cessation of life; Chemicals; Chemistry; Child; Childhood; Clinical; Collection; Country; Data; Development; Disease; Dose; Drug resistance; Economics; Ecosystem; Evaluation; Exhibits; Florida; Fluorescence; Fractionation; Goals; Growth; Individual; Institutes; Investments; Laboratory Research; Lead; Libraries; Malaria; Mammalian Cell; Marine Invertebrates; Marines; Marketing; Methodology; Methods; Microbe; Microbiology; Molecular; Natural Products Chemistry; Nuclear Magnetic Resonance; Parasites; Pharmaceutical Preparations; Plants; Plasmodium falciparum; Population; Porifera; Production; Rain; Research; Research Project Grants; SYBR Green I; Source; Structure; Taxon; Testing; Therapeutic; Therapeutic Index; Toxic effect; Tropical Disease; Universities; Ursidae Family; base; cytotoxicity; experience; forest; interest; killings; liquid chromatography mass spectrometry; liquid chromatography mass spectroscopy; marine natural product; member; microbial; microorganism; mortality; next generation; novel; novel therapeutic intervention; novel therapeutics; response; scaffold; scale up

DESCRIPTION (provided by applicant): There are over 300 million clinical episodes of malaria each year worldwide with over 1 million deaths, primarily in children under 5. Over 41% of the world's population lives in areas where malaria is transmitted. The global economic toll of malaria is staggering. In addition to contributing significantly towards overall childhood mortalit in the poorest nations, the disease is estimated to cause approximately a 1.3% reduction in economic growth in countries that bear a heavy malaria burden. Unfortunately, most of the drugs that are currently being used for malaria treatment were developed more than 30 years ago and many are derivatives of older drugs. In the absence of a large-scale effort to develop novel drugs against malaria, most antimalarials have now become ineffective due to widespread drug resistance. Investment in the discovery of new therapeutics for the treatment of malaria has been sparse and the number of new treatments introduced to the market is correspondingly low. Given the global toll of malaria and the spread of drug resistance, it is important to identif new chemical entities that can be developed into therapeutics for the treatment of drug-resistant malaria. The proposed research project seeks to discover novel chemical entities from marine microbes targeting the malaria parasite is timely and will provide entry into novel therapeutic interventions for the disease. Our approach will be to tap into the chemical and biological diversity of the Harbor Branch Oceanographic Institute Marine Microbial Culture Collection (HBMMCC) as a source of novel bioactive natural products. We will assay a novel library of marine microbe derived extracts for their ability to inhibit the growth of the malaria parasite usig the SYBR Green I Fluorescent assay. Active extracts will be dereplicated using Liquid-chromatography- mass spectroscopy (LC-MS) and NMR methodologies and those with the greatest potential for novel chemistry will be further profiled for their activity against a panel f drug resistant Plasmodium falciparum strains to define potency, and the mammalian cell lines to help assess therapeutic index. Extracts with strong potency against the malaria parasite, low toxicity to mammalian cells and novel chemistry will be taken through bioassay- guided fractionation to identify the structure of bioactive components. The proposed research is significant because at the end of this project we expect to have a portfolio of antimalarial "hits" PUBLIC HEALTH RELEVANCE: Malaria is one of the major tropical diseases afflicting over 300 million and killing about 1 million individuals annually. Majority of the current treatments fo malaria are becoming ineffective because of emergence of drug resistance parasites. Therefore, it is urgent to develop new malaria therapeutics to mitigate this serious problem. The proposed research project seeks to discover novel chemical entities from marine microbes targeting the malaria parasite is timely and will provide entry into novel therapeutic intervention for the disease.

描述（由申请人提供）：全世界每年有超过100万人死亡的疟疾临床发作超过3亿，主要在5岁以下的儿童中。全球41％以上的人口居住在疟疾传播的地区。疟疾的全球经济损失令人震惊。除了为最贫穷国家的童年渴望大大贡献外，据估计，这种疾病的经济增长在承受着沉重的疟疾负担的国家的经济增长约为1.3％。不幸的是，目前用于疟疾治疗的大多数药物是在30年前开发的，许多药物是旧药物的衍生物。在没有大规模开发针对疟疾的新药物的大规模努力的情况下，由于耐药性广泛，大多数抗疟药现在已经无效。在发现新的治疗疟疾的新疗法方面的投资很少，并且引入市场的新疗法数量相应地相应地很低。鉴于疟疾的全球损失和耐药性的传播，重要的是要识别可以发展为治疗耐药疟疾的治疗疗法的新化学实体。拟议的研究项目旨在从针对疟疾寄生虫的海洋微生物中发现新的化学实体，这是及时的，将为该疾病提供新的治疗干预措施。我们的方法是利用港口分支海洋学研究所海洋微生物培养物（HBMMCC）的化学和生物学多样性，作为新型生物活性天然产物的来源。我们将分析一个新型的海洋微生物衍生提取物库，以抑制疟原虫寄生虫的生长usig usig sybr绿色I荧光测定法。活性提取物将使用液相色谱法 - 质量光谱法（LC-MS）和NMR方法论，而具有最大新型化学潜力的人将进一步介绍其针对F耐药性耐药性恶性疟原虫的活性，以降低效力，以降低效率，并有助于评估疗程率。针对疟疾寄生虫，对哺乳动物细胞的低毒性和新型化学的提取物将通过生物测定引导分馏来鉴定生物活性成分的结构。拟议的研究很重要，因为在该项目的结尾，我们预计将拥有抗疟疾的“命中”投资组合 公共卫生相关性：疟疾是折磨超过3亿人，每年杀死约100万人的主要热带疾病之一。由于抗药性寄生虫的出现，目前的大多数治疗方法都变得无效。因此，迫切需要开发新的疟疾疗法来减轻这个严重的问题。拟议的研究项目旨在从针对疟疾寄生虫的海洋微生物中发现新型化学实体，这是及时的，将为该疾病提供新的治疗干预措施。