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Protein Kinases in Streptomyces: Involvement In PROTEIN KINASES IN STREPTOMYCES: INVOLVEMENT IN GROWTH, GLYCOPEPTIDE PRODUCTION AND RESISTANCE. By: JOHN M. NEU A Thesis Submitted to the School of Graduate Studies In Partial Fulfilment of the Requirements for the Degree Doctor of Philosophy McMaster University PROTEIN KINASES IN STREPTOMYCES DOCTOR OF PHILOSOPHY (2002) McMaster University (Biochemistry) Hamilton, Ontario TITLE: Protein Kinases in Streptomyces: Involvement in Growth, Glycopeptide Production and Resistance. AUTHOR: John Morley Neu, B.Sc., M.Sc. (McMaster University) SUPERVISOR: Professor G.D. Wright NUMBER OF PAGES: 229; i-xvi. 11 The History of Medicine • 2000 B. C. - Here, eat this root a 1000 A.D. - That root is heathen. Here, scry this prcryer. • 1850 A.D. - That prcryer is superstition. Here, drink this potion. • 1920 A.D. - That potion is snake oil. Here, swallow this pill. a 1945 A.D. - That pill is ineffective. Here, take this penicillin. • 1955 A.D. - Oops .... bugs mutated. Here, take this tetracycline. • 1960-1999- 39 more "oops"... Here, take this more powerfol antibiotic. • 2000 A.D. - The bugs have won! Here, eat this root. -Anonymous 111 Abstract With the recent crisis in hospital-acquired infections, a renewed sense of urgency for studying bacterial species carrying antibiotic resistance determinants has developed. Much of the focus has been centered on the glycopeptide antibiotics including vancomycin, which represent the last main line of defense against many hospital-acquired infections. These clinically pivotal antibiotics are produced by filamentous bacteria in the order Actinomycetes including the genus Streptomyces. The investigations presented in this thesis were undertaken to address fundamental questions of glycopeptide production and resistance in the glycopeptide-producing Streptomyces toyocaensis NRRL 15009 and non-producing Streptomyces coeficolor A3(2). Specifically, questions with respect to the regulation of antibiotic production and resistance have been addressed in light of the relatively recent isolation of protein kinase genes with high similarity to those of eukaryotic origin. A link between glycopeptide production, resistance and protein phosphorylation in S. toyocaensis NRRL 15009 is presented as a basis for a subsequent degenerate PCR strategy to clone putative protein kinase genes from this organism. Using the PCR strategy four putative protein kinase gene fragments were cloned and one of these, stoPK-1 was isolated in its entirety and characterized by biochemical and genetic methods. Analysis of StoPK-l revealed a bona fide serine/threonine protein kinase with localization to membrane fractions. Disruption of the genomic stoPK-l gene in S. toyocaensis NRRL 15009 brought about an increased sensitivity to oxidative stress lV which could be reversed by supplying stoPK-l in trans, but not with a catalytically dead mutant, suggesting a role for the active kinase in responding to oxidative stress in S. toyocaensis NRRL 15009. Additionally, studies examining glycopeptide resistance were undertaken through genomic gene disruption and complementation on the previously isolated vancomycin resistance gene cluster (vanHAX), supporting a role for this cluster in Streptomyces similar to its function in yancomycin resistant gnterococcus (VRE). Furthermore, analysis of Streptomyces DNA sequences revealed putative two component regulatory systems composed of histidine kinase and response regulator pairs associated with the vanHAX genes in S. coelicolor A3(2) and the glycopeptide biosynthesis genes in S. toyocaensis NRRL 15009. These putative VanRS systems share homology to proteins shown to be critical for inducible resistance in VRE, and these observations encouraged an assessment of the response regulator (VanR) homologue in regulating resistance in S. coelicolor A3(2). The results of these studies support the conclusion that the regulation of vancomycin resistance in Streptomyces is similar to Enterococcus and provide further evidence that these soil-born bacteria may be the original source of the clinically important resistance genes. v Dedication I would like to dedicate this work to my dad and mom, Nic and Anne Neu, whose commitment to my education made possible the work undertaken here. And to my wonderful wife Charmaine, whose love and support inspire me to achieve higher goals in all areas of life. vi Acknowledgements Firstly I wish to acknowledge the tireless supervision of Dr. Gerard Wright whose love of scientific inquiry is contagiously inspiring. My greatest respect and admiration goes to him for his patience and caring. I also thank my wife Charmaine for her understanding of the "odd" hours that must be kept when investigating matters of scientific importance, and for her love and support through the past years. A special thanks goes to Dr. Justin Nodwell for his advise and expertise with matters pertaining to Streptomyces. I also thank my other supervisor committee members Dr. David Andrews and Dr. Astrid Petrich for their advise and direction over the work period. Finally I thank the members of my laboratory for making the time there fun and exciting, with special mention to Gary Marshall for his ever encouraging help and advise in matters pertaining to Streptomyces. Vll Table of Contents Abstract ............................................................................................................................. iv Dedication ......................................................................................................................... vi Acknowledgements ......................................................................................................... vii List of Figures ................................................................................................................. xiii Lists of Tables ................................................................................................................. xvi Chapter 1. Introduction ................................................................................................... 1 1.1. ANTIBIOTICS AND ANTIBIOTIC RESISTANCE ............................................................... 2 1.2. STRUCTURE AND ACTIVITY OF GLYCOPEPTIDE ANTIBIOTICS ...................................... 7 1.2.1. Glycopeptides Classification .......................................................................... 7 1.2.2. Dimerization ................................................................................................... 9 1.2.3. Peptidoglycan Assembly .............................................................................. 10 1.3 . GLYCOPEPTIDE ANTIBIOTIC RESISTANCE ................................................................. 12 1.3.1. Resistance in Enterococcus ........................................................................... 12 1.3.2. Resistance in Streptomyces ........................................................................... 14 1.3.3. Regulation of Glycopeptide Antibiotic Resistance ....................................... 16 1.4. GLYCOPEPTIDE ANTIBIOTIC BIOSYNTHESIS .............................................................. 19 1.4.1. Non-ribosomal Peptide Synthases ................................................................ 19 1.4.2. Regulation of Glycopeptide Antibiotic Production ...................................... 20 1.5. PROJECT GOALS AND STRATEGIES ............................................................................ 22 1.5.1. Characterizaton of conditions for A47934 antibiotic production ................. 22 1.5.2. Role of protein phosphorylation in A47934 production and resistance ....... 22 1.5.3. Cloning and characterization of protein kinases in S. toyocaensis . .............. 23 1.5.4. Necessity of the vanHAX cluster in S. toyocaensis ...................................... 24 1.5.5. Role of the vanHAX-associated two component system in S. coelicolor .... 24 1.6 REFERENCES ............................................................................................................. 25 vm Chapter 2. Regulation of A47934 Glycopeptide Antibiotic Production and Resistance in Streptomyces toyocaensis NRRL 15009 .............................. 33 2.1. BACKGROUND ........................................................................................................... 34 2.1.1. Secondary Metabolism in Streptomyces toyocaensis: Temporal and Nutrient Requirements .................................................................................................. 34 2.1.2. Antibiotic Drug Production and Phosphorylation .......................................... 35 2.1.3. Antibiotic Drug Production and Gene Expression ......................................... 37 2.2. MATERIALS AND METHODS ...................................................................................... 40 2.2.1. Organisms and Culture Conditions ................................................................ 40 2.2.2. A47934 and Other Antibiotic Bioassays ....................................................... 41 2.2.3 re2p]-ATP Labeling of S. toyocaensis NRRL 15009 cell extracts............... 42 2.2.4. Hl2p04 Whole Cell Labeling ........................................................................ 43 2.2.5. Phospho amino acid analysis .......................................................................... 44 2.2.5.1 PhosphoSer, phosphoThr and phosphoTyr ........................................... 44 2.2.5.2. PhosphoHis ..........................................................................................
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