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Metabolomic Profiling of Natural Products from Two Tolypocladium Fungal Species As Part of an Evolutionary Genomics Study

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Metabolomic Profiling of Natural Products from Two Tolypocladium Fungal Species As Part of an Evolutionary Genomics Study AN ABSTRACT OF THE THESIS OF Bailey J. Dickey for the degree of Master of Science in Pharmacy presented on August 21, 2015. Title: Metabolomic Profiling of Natural Products from Two Tolypocladium Fungal Species as Part of An Evolutionary Genomics Study Abstract approved: ______________________________________________________ Kerry L. McPhail This thesis describes an investigation of the natural products chemistry of two fungal species of the genus Tolypocladium. Natural products are small organic molecules that are considered non-essential for cell growth and reproduction, and thus part of secondary metabolism. Chemical profiling of these secondary metabolites using a combination of high-performance liquid chromatography (HPLC) and mass spectrometry (MS), as well as 1H nuclear magnetic resonance (NMR) spectroscopy, identified a number of known and unknown natural products of Tolypocladium inflatum and T. geodes. In particular, putative new peptaibols were detected by LC- MS/MS profiling, although these data were insufficient for structural characterization. To determine the effect of a putative secondary metabolite regulator, comparative metabolomic profiling was performed of T. inflatum wild-type and a knockout mutant in which the genes for a homolog of the histone methyltransferase KMT6 had been deleted. A preliminary result on the deletion of the kmt6 gene homolog suggests a knockdown of CsA and possibly the putative new peptaibols. Finally, to demonstrate the potential of T. inflatum to produce medicinally-relevant molecules with new biological activities, extracts and fractions were screened against the human pathogen Neisseria gonorrhoeae. Some test samples appeared to possess potent activity and, suggesting that they contain compounds, which inhibit the growth of N. gonorrhoeae. ©Copyright by Bailey J. Dickey August 21, 2015 All Rights Reserved Metabolomic Profiling of Natural Products from Two Tolypocladium Fungal Species as Part of An Evolutionary Genomics Study by Bailey J. Dickey A THESIS submitted to Oregon State University in partial fulfillment of the requirements for the degree of Master of Science Presented August 21, 2015 Commencement June 2016 Master of Science thesis of Bailey J. Dickey presented on August 21, 2015 APPROVED: Major Professor, representing Pharmacy Dean of the College of Pharmacy Dean of the Graduate School I understand that my thesis will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my thesis to any reader upon request. Bailey J. Dickey, Author ACKNOWLEDGEMENTS Firstly, I would like to thank my family. The tri-generation trio: my grandfather, father and brother who have always been very supportive throughout my graduate career. They have helped me to reach my full potential and to achieve the best. As well as my mother, the best storyteller who articulates detailed descriptions of her travels, reminding me that life is full of adventure. My grandmother Bonnie, a strong hearted women with a great sense of humor that has gave me the courage to strive for a career in the sciences and to never give up using the phrase,“ It’s not over until the heavy lady sings”! A big thank you also goes to my dog Bebe for always being their by my side, quite literally. Most of all however, to my boyfriend who has pushed me to do my best, been there through the tough times and taught me that a cup of tea solves everything. I would also like to thank Dr. Kerry McPhail for giving me the opportunity to come to OSU. She has been a great source for guidance and I truly appreciate all her help throughout my project. I would also like to extend my gratitude to Dr. Joey Spatafora and Rheannon Arvidson for their support and all the genomic work that was contributed to the project as well as, Dr. Sandra Loesgen, Dr. Taifo Mahmud, Dr. Benjamin Philmus and Dr. Patrick Videau who have also proven useful sources of conversation and mentorship through the course of my masters degree. I would also like to thank funding provided by the National Science Foundation. Lastly, to my lab mates and friends Igor, Dorota and Arun who have put up with me for the past two years and have been the best roommates I could ask for. CONTRIBUTION OF AUTHORS The Spatafora Lab provided all Tolypocladium species and all the phylogenetic studies, with contributions from Dr. Joey Spatafora, Rheannon Arvidson, Dr. Alisha Quandt and Dr. Kathryn Bushley. Dr. Kerry McPhail contributed throughout the metabolomic profiling of Tolypocladium as well as, previous work contributed from Mariko Nonogaki. Additionally, the Sikora Lab performed the Neisseria gonorrhoeae growth inhibitory assay contributed from Dr. Alexandra Sikora and Igor Wierzbicki. TABLE OF CONTENTS Page CHAPTER ONE: General Introduction ......................................................................... 1 Natural Products and their Role in Human Health and Agriculture ........................... 2 Historically Important Fungal Natural Products .......................................................... 3 Metabolomic Profiling as a means of isolating Fungal Natural Products....................6 Overview of the Evolutionary Biology of the Fungal Order Hypocreales.................11 Inter and intra-kingdom host shifts within the Hypocreales…………...……….......12 Known Secondary Metabolites of Tolypocladium.....................................................13 Project Aims...............................................................................................................20 CHAPTER TWO Metabolomic profiling of Tolypocladium inflatum and T. geodes........................................................................................................................22 Introduction ............................................................................................................... 23 Methods and Materials .............................................................................................. 24 Results and Discussion ............................................................................................. 27 Conclusion ................................................................................................................ 44 CHAPTER THREE: Loss of cyclosporin A Production in a Genetic Knockout of a kmt6 methyltransferase homolog in T. inflatum.......................................................................46 Introduction ............................................................................................................... 47 Methods and Materials...............................................................................................51 Results and Discussion ............................................................................................. 56 Conclusion..................................................................................................................69 Bibliography ............................................................................................................. 72 LIST OF FIGURES Figure Page Figure 1.1 Structures of penicillin G, cephalosporin C, fusidic acid griseofulvin, and mevinolin ................................................................................................................ 4 Figure 1.2 Structures of fusarisetin A and macrosphelide B ......................................... 5 Figure 1.3 An example of metabolomics profiling taken from Müller et al. in the discovery of myxoprincomide.........................................................................................8 Figure 1.4 Structures of chlorinated (top) and brominated (bottom) anthraquinones with numbering scheme designating the name .............................................................. 9 Figure 1.5 Structure of fellutamide B .......................................................................... 10 Figure 1.6 Phylogeny of Hypocreales .......................................................................... 13 Figure 1.7 Structure of cylosporin A ........................................................................... 15 Figure 1.8 Structure of FR190293 ............................................................................... 16 Figure 1.9 Structure of efrapeptin D ............................................................................ 17 Figure 1.10 Structures of the peptaibols LP237-F5, -F7, and -F8 ............................... 18 Figure 1.11 Structures of fumonisins B2 and B4 ......................................................... 19 Figure 1.12 Structure of tolypoalbin ............................................................................ 19 Figure 2.1 LC-MS spectrum of putative peptaibols from T. inflatum ......................... 24 Figure 2.2 Diagram of reverse phase extraction method ............................................. 25 Figure 2.3 LC-MS/MS spectrum of putative peptaibols in PDB ................................. 29 Figure 2.4 LC-MS/MS spectrum of putative peptaibols in SM ................................... 30 Figure 2.5 LC-MS/MS spectrum of T. inflatum cultured in SM showing CsA. .......... 32 Figure 2.6 LC-MS/MS spectrum of T. geodes cultured on PDA showing CsA .......... 33 Figure 2.7 Metabolomic profiling identified known fumonisins in the organic extract of T. inflatum ................................................................................................................ 34 LIST OF FIGURES CONTINUED Figure Page Figure 2.8 Metabolomic profiling identified fumonisins
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