Novel Antimalarials from Marine Microbial Natural Products

描述（由申请人提供）：全世界每年有3亿多疟疾临床病例，其中100多万人死亡，主要是5岁以下儿童。超过41%的世界人口生活在疟疾传播地区。疟疾造成的全球经济损失是惊人的。除了对最贫穷国家的总体儿童死亡率造成重大影响外，据估计，该病还使疟疾负担沉重的国家的经济增长减少约1.3%。不幸的是，目前用于治疗疟疾的大多数药物都是30多年前开发的，其中许多是旧药物的衍生物。在没有大规模努力开发抗疟疾新药的情况下，由于广泛的耐药性，大多数抗疟疾药物现在已经无效。在发现治疗疟疾的新疗法方面的投资很少，推向市场的新疗法的数量也相应较少。鉴于疟疾在全球造成的死亡和耐药性的蔓延，重要的是确定可以开发成治疗耐药疟疾的疗法的新化学实体。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，并将为该疾病提供新的治疗干预措施。我们的方法将是利用海港海洋研究所海洋微生物培养收集（HBMMCC）的化学和生物多样性作为新型生物活性天然产品的来源。我们将使用SYBR Green I荧光法检测一个新的海洋微生物提取库，以检测它们抑制疟疾寄生虫生长的能力。活性提取物将使用液相色谱-质谱（LC-MS）和核磁共振（NMR）方法进行分离，而那些具有最大新化学潜力的提取物将进一步对其对一组耐药恶性疟原虫菌株的活性进行分析，以确定其效力，并对哺乳动物细胞系进行分析，以帮助评估治疗指数。利用生物测定引导分离技术鉴定具有抗疟原虫活性强、对哺乳动物细胞毒性低、化学成分新颖等特点的提取物。拟议中的研究意义重大，因为在这个项目结束时，我们希望有一个抗疟疾“热门”组合。

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.