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SHETTY-DISSERTATION-2012.Pdf (5.049Mb) STRUCTURAL INVESTIGATION OF MYCOBACTERIUM TUBERCULOSIS DRUG TARGETS AND THE EVALUATION OF NATURAL PRODUCTS DERIVED INHIBITOR CANDIDATES A Dissertation by NISHANT DEVIDAS SHETTY Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved by: Chair of Committee, James C. Sacchettini Committee Members, Kevin Burgess Daniel Romo Thomas R. Ioerger Head of Department, Simon W. North December 2012 Major Subject: Chemistry Copyright 2012 Nishant Devidas Shetty ABSTRACT This dissertation uses two different approaches to the identification of inhibitors of Mycobacterium tuberculosis (Mtb) - a structure-based drug discovery approach and a high-throughput screening of natural product libraries based approach. In the structure- based approach the structural characterization of Mtb s-adenosylhomocysteine hydrolase (SAHH) enzyme as a drug target using x-ray crystallography is described. Crystal structure of Mtb SAHH protein was solved in complex with the substrate adenosine and the product s-adenosylhomocysteine at 1.6 Å and 2.0 Å resolutions respectively. Additionally, crystal structures of Mtb SAHH in complex with inhibitors, aristeromycine (ARI), deazaadenosine and 2-fluoroadenosine were also solved at 2.1 Å, 2.2 Å and 2.4 Å resolutions respectively. The complex structure with ARI is the first structure reported and confirms the proposed type-I mechanism based inhibition of Mtb SAHH. Differences in the active site of Mtb SAHH and human SAHH are identified and the design of lead molecules selective towards the Mtb SAHH is described using the fragment-based lead identification method. The structural characterization of a nitrogen regulatory Mtb PII protein is also described. The crystal structure of Mtb PII protein in the apo form and adenosine triphosphate bound form was solved to 1.4 Å and 2.4 Å resolutions respectively. The crystal structures suggest an alternate annotation of the protein as GlnK and also provide insights into the mechanism of action of the Mtb PII protein. The Mtb PII protein plays a versatile role in the nitrogen regulatory pathway of the microorganism and represents a potential drug target in Mtb. ii Through the alternate approach to drug discovery involving the screening of natural products for whole-cell bactericidal activity a novel natural product inhibitor of Mycobacterium tuberculosis and Mycobacterium smegmatis was isolated, purified and characterized. Challenges encountered in the large scale data processing involving high- throughput screening and high performance liquid chromatography (HPLC) / mass spectrometric analysis in terms of prioritizing the crude extracts, the HPLC fractions and the masses corresponding to the compounds of interest are listed and methods for data reduction and efficient da ta analysis are presented. The successful identification of a novel natural product with inhibitory activity towards the human and yeast proteasome in an in-vitro enzyme assay is also described. The novel polyphenolic natural product was discovered through the screening of crude extracts in a proteasome targeted in vitro enzyme assay followed by activity based fractionation, isolation, purification and structure elucidation using analytical techniques. A technique for the chemical derivatization of a mixture of unknown secondary metabolites in crude extracts is also described, which can potentially increase the existing diversity of natural product libraries used in high-throughput screening. iii DEDICATION To Ajja and Amma iv ACKNOWLEDGEMENTS I would like to start by acknowledging my graduate adviser, Dr. James C. Sacchettini, for giving me the opportunity to work in a wonderful research laboratory and for making available all the tools necessary to conduct my research, my committee members Dr. Kevin Burgess, Dr. Daniel Romo, Dr. Thomas Ioerger, past and present members of the Sacchetini lab, Siaska Castro, Lacy Snow, Dr. Frank Raushel, Dr. Andreas Holzenburg, Dr. Joel Freundlich and Dr. Dwight Baker. In the structure-based approach to drug discovery, I would like to thank my mentors, Dr. Sudarshan (Sid) Sridharan, Dr. Arulandu (Sam) Arockiasamy, Dr. Satheesh Palaninathan, Dr. Gokulan Kuppan and Dr. Manchi Reddy. I would like to thank my co- workers Josh Owen, Misty Watson, Dmitri Verkhoturov, Tr isha Star and Priyanka Desai for helping me the bench work. In the natural products projects I would like to acknowledge Stephanie Swanson for her help with establishing the growth conditions of M. smegmatis cells and optimizing the lysis methods, Dr. Terry J. Gentry and Amanda Engledow for the 16SrDNA sequencing, Dr. Larry Dangott for his help with liquid chromatography, Wen Dong, Erika Delgado and Steven Lihing for their efforts in whole-cell screening studies on mc27000 and mc2155 strains of M. tuberculosis and M. smegmatis cells respectively as well as on the human cancer cell lines, Liam Guthrie for whole-cell screening studies on the yeast model, Saccharomyces cerevisiae and Candida albicans. Wayne Harshbarger and Su Tang for human and yeast proteasome in vitro enzyme assays, Dr. Xiangming (Sean) Kong, Dr. Vijay Gawandi and Dr. Howard v Williams for their assistance with 1H NMR, 13C NMR, 2D NMR, STD NMR spectroscopy and structure elucidation, the staff of Chemistry Department (especially Sandy Manning) and the staff of Biochemistry and Biophysics department for their patience and understanding. I would like to specially acknowledge Dr. Dwight Baker for his constant guidance and support in the natural products research, and for all his encouragement. He has been a great mentor to me and I have learned a lot from him. I would also like to thank my good friends Mallikarjun Lalgondar, Dr. Jiney Jose and Dr. Praveen Boopalachandran for all the useful discussions and for their support and motivation throughout our graduate studies together at Texas A & M University. Lastly, I would like to say a big thanks to my parents for their moral support and encouragement and to my dear wife, Rashmi for her patience and love. vi NOMENCLATURE TB Tuberculosis BC Before Christ BCE Before the Common Era WHO World Health Organisation Mtb Mycobacterium tuberculosis BCG Bacilli Calmette-Guérin NIAID National Institute of Allergy and Infectious Diseases CDC Center for Disease Control TBSGC Tuberculosis Structural Genomics Consortium XDR Extensively Drug Resistant M. smeg Mycobacterium smegmatis E. coli Escherichia coli Pf Plasmodium falciparum M. jann Methanococcus jannaschii SAHH S-adenosyl-L-homocysteine Hydrolase SAH S-adenosylhomocysteine NAD+ Nicotinamide Adenine Dinucleotide (oxidized form) NADH Nicotinamide Adenine Dinucleotide (reduced form) SAM S-adenosylmethionine HCY Homocysteine vii ADO Adenosine 2OG 2-Oxoglutarate Gln Glutamine GS Glutamine Synthetase GOGAT Glutamine: 2-Oxoglutarate Aminotransferase Glu Glutamate / Glutamic acid AmtB Ammonium Transporter protein Lys Lysin Asp Aspartate / Aspartic acid Leu Leucin Thr Threonine GlnE / Atase Adenylyl Transferase GlnD Uridylyl Transferase BME β – mercaptoethanol HTS High-Throughput Screening ARI Aristeromycin DZA 3-Deazaadenosine 2FA 2-Fluoroadenosine PCR Polymerase Chain Reaction RMSD Root Mean Square Deviation PDB Protein Data Bank His Histidine viii Gly Glycine Ala Alanine Arg Arginine Asn Asparagine Cys Cystine Ile Isoleucine Met Methionine Phe Phenylalanine Pro Proline Ser Serine Trp Tryptophan Tyr Tyrosine Val Valine ETA Ethylthioadenosine OH Hydroxyl SDS PAGE Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis EDTA Ethylenediaminetetraacetic Acid PEG Polyethylene Glycol DSF Differential Scanning Fluorimetry STD NMR Saturation Transfer Difference Nuclear Magnetic Resonance ATP Adenosine Triphosphate ADP Adenosine Diphosphate ix S. griseus Streptomyces griseus DMSO Dimethyl Sulfoxide HPLC High Performance Liquid Chromatography LC Liquid Chromatography UV Ultraviolet PDA Photo Diode Array FA Formic Acid MS Mass Spectrometry m/z Mass to Charge Ratio HRMS High Resolution Mass Spectrometry TOF Time-of-Flight Q-TOF Quadrupole Time-of-Flight DNP Dictionary of Natural Products NMR Nuclear Magnetic Resonance IC50 50 % Inhibitory Concentration MIC Miminal Inhibitory Concentration DTNB 5,5'-dithiobis-(2-nitrobenzoic acid) / Ellman’s reagent ESI Electrospray Ionization DEPT Distortionless Enhancement by Polarization Transfer SFC Supercritical Fluid Chromatography x TABLE OF CONTENTS Page ABSTRACT .............................................................................................................. ii DEDICATION .......................................................................................................... iv ACKNOWLEDGEMENTS ...................................................................................... v NOMENCLATURE .................................................................................................. vii TABLE OF CONTENTS .......................................................................................... xi LIST OF FIGURES ................................................................................................... xiv LIST OF TABLES .................................................................................................... xx CHAPTER I INTRODUCTION AND LITERATURE REVIEW ............................ 1 The History of Tuberculosis ................................................................. 1 Cause of TB and Early Treatment Methods ......................................... 5 Modern Treatment Methods ................................................................
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