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

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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.