K KYEREMEH, Ghana - Development of Novel Therapeutics for Parasite Infections and Cancer by Multi-step Microbial Biodiscovery Processes and iChip

该项目旨在利用撒哈拉以南非洲巨大的微生物生物多样性，建立一个大型生物合成微生物库和一个新型化学结构管道，可用于开发治疗撒哈拉以南非洲主要流行的感染、癌症和寄生虫病的药物。该项目将利用该小组实验室中各种完善的生物测定方法来筛选撒哈拉以南地区微生物的微生物化学多样性。最重要的是，我们团队成员已经建立了高标准执行某些功能的能力，包括：从土壤，植物，鱼类，螃蟹和肉食性软体动物中分离和纯化大量自由生活的微生物；化学分析，以确定这些微生物产生的分子；分子的分离与表征；利用微生物全基因组序列进行生物合成基因簇、生物信息学、敲除和异源表达沉默基因以产生新的代谢物。在这项研究中，对选择性和有效活性的要求非常重要，因此低水平的新型微生物化学结构必须能够杀死寄生虫或细菌，而不会对正常的人类细胞产生影响。该项目中获得的所有分子的生物活性谱将被详细评估，从而为发现新的抗癌药物提供可能。我们将收集总共300种新的西非微生物菌株，分离、表征和确定它们在正常实验室培养条件下表达的分子的抗生素、抗寄生虫和抗癌特性。最重要的是，我们将找到方法来诱导这些微生物表达一些在正常实验室条件下不易产生的分子，方法是在许多定制的培养基和培养条件下培养它们，与共生真菌共培养，以及存在化学线索，如一氧化氮，已知可以激活沉默的生物合成基因簇的转录。此外，我们将使用生物信息学来识别编码强效抗生素、抗寄生虫和抗癌分子的沉默基因簇，在易于生长的细菌中敲除和异种表达这些基因，从而产生足够数量的化合物。该项目将以获得的化学结构为基础，创造一系列具有相同活性但具有不同和更改进的药物特性的衍生物和类似物。这将有助于确定一种“铅”分子，这种分子具有强大的活性、低毒性、能够安全给药并准备在动物模块中进行试验。

This project seeks to exploit the huge microbial biodiversity of sub-Saharan Africa to create a large library of biosynthetically talented microbes and a pipeline of novel chemical structures that can be used for the development of drugs for infections, cancer and parasitic diseases that are largely endemic to sub-Saharan Africa. The project will take advantage of different well established bioassays in the laboratories of this team to screen the microbial chemical diversity of sub-Saharan microbes. What is most important, is the already well-established ability of members of our team to perform to a very high standard certain functions including: isolation and purification of a large number of free-living microbes from soils, plants, fishes, crabs and carnivorous molluscs; chemical profiling to determine molecules that are produced by these microbes; isolation and characterization of molecules; exploitation of whole microbial genome sequences for biosynthetic gene clusters, bioinformatics, knockout and heterologous expression of silent genes for the production of novel metabolites. The requirement of selective and potent activity is very important in this research and hence low levels of novel microbial chemical structures must be able to kill parasites or bacteria without having an effect on normal human cells. The biological activity profiles of all the molecules obtained in the project will be evaluated into detail giving the possibility for the discovery of new anticancer agents.We will assemble a total of 300 novel West African microbial strains, isolate, characterize and determine the antibiotic, antiparasitic and anticancer properties of the molecules they express under normal laboratory culture conditions. Most importantly, we will find ways to induce these microbes to express some of the molecules that are not easily produced under normal laboratory conditions by growing them in many customized media and culture conditions, co-culture with co-associating fungi, and presence of chemical cues like nitric oxide known to activate transcription of silent biosynthetic gene clusters. Furthermore, we will use bioinformatics to identify silent gene clusters that encode for potent antibiotic, antiparasitic and anticancer molecules, knockout and heterologously express these genes in easy-to-grow bacteria that allows the production of compounds in sufficient quantities. This project will build on the chemical structures obtained to create a series of derivatives and analogues that are equally active but have different and more improved characteristics as drugs. This will facilitate the identification of a "lead" molecule with potent activity, low toxicity, the ability to be administered safely and ready for testing in animal modules.