Ongoing antibiotic drug discovery is vital as antimicrobial resistance continues to be a significant issue faced in the clinic. Natural products have long been a highly productive source to mine for new antimicrobials. While it has been challenging to discover new and unique antimicrobial natural products, numerous drugs have been derived from studying how natural products function as secondary metabolites. Previous studies suggested that screening natural product extract fraction libraries for antimicrobials can be more productive than screening crude extracts alone. These studies from large industrial enterprises are generally not directly portable to an academic setting due to significant infrastructure costs. We developed a screening platform consisting of low pressure reversed-phase chromatographic separation of methanolic extracts of bacteria and fungi to generate a prefractionated natural product library. This platform is suitable for academic labs to screen for antimicrobial compounds. A large growth inhibitor screen against multiple pathogens and lab strains of microbes was conducted to assess the validity of the advantages of screening fraction libraries versus crude extract libraries and to search for potential new drug-like compounds. Hits were investigated for reproducibility, isolated, and purified. One compound was discovered in an antifungal screen which may be a novel lipopeptide. / Thesis / Master of Science (MSc) / To combat the growing antibiotic resistance crisis, new strategies for drug discovery must be investigated and implemented. Natural products from bacteria and fungi have long been a source of critically important drugs. Prior research suggests that looking for vital natural products in fraction libraries can be more productive than screening crude extracts. Here the development and assessment of a fractionation library suitable for an academic lab's ingrained limitations are described. Assessing the library indicates an increased hit rate on screening fractions compared to crude extract. Furthermore, pursuing these hits may have revealed a novel antifungal lipopeptide.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27282 |
| Date | January 2021 |
| Creators | Pallant, Daniel |
| Contributors | Wright, Gerard, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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