21st Century Microbial Natural Product Drug Discovery in the African Context: A combined Atomic Force Microscopy and Computational Approach for the Structural Elucidation of Novel Compounds
Oral-Virtual · Withdrawn
Abstract
We proposed intensive/sustained research to discover NDE for NTDs and won the 2018 jointly funded UK-MRC/DFID/FCDO Concordat agreement, Africa-Research-Leader-ARL Award:
‘Development of NovelTherapeutics for Parasite Infections and Cancer by Multi-step Microbial Biodiscovery Processes and iChip’. The team sampled soils/sediments/invertebrates/plants from >250 GPS-coordinates in nationwide Ghana including mangroves, waterfalls and national parks. A library of >300 environmental-microbial strains with 100% novel-biodiversity was generated. From this we have so far screened >600 extracts against a panel of 15-cytotoxicity, 6-pathogenic bacteria, 1 -fungus, 1-yeast cell lines, 3-antiparasitic and 2-antiviral bioassay screen-platforms.
About 150 of our strains produce potent-bioactive extracts and strain-by-strain we have isolated and determined the structures of >200 compounds produced under normal laboratory-rich-fermentation cultures. Biosynthetic-pathways have been studied and silent/cryptic gene encoded compounds isolated through bioengineering-heterologous expression and/or cultivation-based, chemical, and biological elicitors.
Nevertheless, this project has been largely hindered and affected by the extreme complexity of the compounds that we isolate from these Ghanaian strains. While difficulties such as the isolation of increasingly small amounts of novel metabolites, the inability to obtain quality NMR and X-ray data amongst others have been 2 persistent, the main drawbacks have been related to the i) confirmation of the correct regiochemistry, and stereochemistry and the ii) determination of structure in compounds without spin-systems such as fully aromatic naturally occurring alkaloids.
Herein, we explain some of the difficulties we have experienced in the structure determination of microbial natural products here at the department and how atomic force microscopy could provide breakthroughs in the structure determination process. We use the previously determined structure of breitfussin A by Jaspars et. al. to illustrate our case.
‘Development of NovelTherapeutics for Parasite Infections and Cancer by Multi-step Microbial Biodiscovery Processes and iChip’. The team sampled soils/sediments/invertebrates/plants from >250 GPS-coordinates in nationwide Ghana including mangroves, waterfalls and national parks. A library of >300 environmental-microbial strains with 100% novel-biodiversity was generated. From this we have so far screened >600 extracts against a panel of 15-cytotoxicity, 6-pathogenic bacteria, 1 -fungus, 1-yeast cell lines, 3-antiparasitic and 2-antiviral bioassay screen-platforms.
About 150 of our strains produce potent-bioactive extracts and strain-by-strain we have isolated and determined the structures of >200 compounds produced under normal laboratory-rich-fermentation cultures. Biosynthetic-pathways have been studied and silent/cryptic gene encoded compounds isolated through bioengineering-heterologous expression and/or cultivation-based, chemical, and biological elicitors.
Nevertheless, this project has been largely hindered and affected by the extreme complexity of the compounds that we isolate from these Ghanaian strains. While difficulties such as the isolation of increasingly small amounts of novel metabolites, the inability to obtain quality NMR and X-ray data amongst others have been 2 persistent, the main drawbacks have been related to the i) confirmation of the correct regiochemistry, and stereochemistry and the ii) determination of structure in compounds without spin-systems such as fully aromatic naturally occurring alkaloids.
Herein, we explain some of the difficulties we have experienced in the structure determination of microbial natural products here at the department and how atomic force microscopy could provide breakthroughs in the structure determination process. We use the previously determined structure of breitfussin A by Jaspars et. al. to illustrate our case.
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Presenters
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Kwaku Kyeremeh
- University of Ghana