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The use of mass spectrometry to characterize the metabolic output of bacterial pathogens


The overall theme of this thesis is the use of mass spectrometry to answer questions of biological relevance. The thesis begins by informing the reader on the basics of mass spectrometry and associated tools with an introductory chapter. Chapter 2 describes collaborative work performed between three labs at UCSD, the Jack E. Dixon, Victor Nizet and Pieter C. Dorrestein labs. The project was initiated by the use of comparative genomics to discover a widely distribution toxin biosynthetic gene cluster. Molecular and biochemical analysis of a two members of the conserved family, namely Group A Streptococcus and Clostridium Botulinum, demonstrated the organisms indeed contained similar cellular machinery for the biosynthesis of ribosomally encoded peptides putatively containing thiazole and (methyl)-oxazole moieties. Chapter 3 continues characterizing the widely distributed family of toxins specifically characterizing the gene cluster within the bacterium C. Botulinum. The work describes the use of mass spectrometry to obtain structural evidence, verifying the biosynthetic gene cluster indeed produces heterocycles as hypothesized by the genomic studies. Additionally, the work uses biochemical and genetic approaches to characterize a novel [Beta]-hemolytic, cytolytic toxin in two Clostridia species. Chapter 4 introduces the method of imaging mass spectrometry (IMS) of microbial colonies. Although IMS is not a novel technique, very few reports had used the technology to investigate the microbial kingdom. The work within chapter 4 describes an IMS survey performed on a vast number of differential microbes to visualize their associated metabolic output. The goal was to show that IMS is an amenable technique that can be applied to a diverse number of microbes. Chapter 5 goes beyond the proposal set forth in chapter 4, as IMS was used to visualize the interaction between two well characterized model bacterial systems, the probiotic bacterium Bacillus subtilis and the bona fide human pathogen methicillin resistant Staphylococcus aureus (MRSA). Imaging mass spectrometry showed directional release of compounds by the probiotic organism B. subtilis that have antibiotic effects against MRSA giving insight into the potential mode of action for probiotic organisms

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