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http://hdl.handle.net/11375/22190
Title: | RESISTANCE PROFILING OF MICROBIAL GENOMES TO REVEAL NOVEL ANTIBIOTIC NATURAL PRODUCTS |
Authors: | Walker, Chelsea |
Advisor: | Magarvey, Nathan |
Department: | Biochemistry and Biomedical Sciences |
Keywords: | Antibiotic Discovery;Natural Products |
Publication Date: | 2017 |
Abstract: | Microbial natural products have been an invaluable resource for providing clinically relevant therapeutics for almost a century, including most of the commonly used antibiotics that are still in medical use today. In more recent decades, the need for new biotherapeutics has begun to grow, as multi-drug resistant pathogens continue to emerge, putting into question the long-term efficacy of many drugs that we routinely depend on to combat infectious diseases. To affect this growing medical crisis, new efforts are being applied to computationally mine the genomes of microorganisms for biosynthetic gene clusters that code for molecules possessing anti-microbial activities that circumvent known resistance mechanisms. To this end, cutting-edge software platforms have been developed that can identify, with high predictive accuracy, microbial genomes that code for natural products of potential interest. However, with such analyses comes the need to thoroughly vet each predicted gene cluster, to identify those high-value candidate molecules that are not associated with known resistance mechanisms. In this work, a new strategy was developed that involved cataloguing all known ‘self-resistance’ mechanisms encoded by natural product producing microorganisms, which protect the producer from the highly toxic effects of their secreted anti-microbial agents. This collection of resistance data was leveraged and used to engineer an automated software-based pipeline that interrogates biosynthetic gene clusters and relates them to previously identified resistance mechanisms. Gene clusters that are revealed to be independent of known resistance mechanisms can then be flagged for further chemical and biological study in the laboratory. Such in-depth interrogations of microbial genomes aim to help reveal the full biological repertoire of antibiotics yet to be discovered from microorganisms, and will lead to the development of the next generation of biotherapeutics to quell the growing medical crisis of antibiotic-resistance among human pathogenic organisms. |
URI: | http://hdl.handle.net/11375/22190 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Walker_Chelsea_G_finalsubmission2017June_MasterofScience.pdf | 3.92 MB | Adobe PDF | View/Open |
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