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APPLICATION of STRUCTURE ACTIVITY RELATIONSHIPS of the MYCOBACTERIUM TUBERCULOSIS BETA-LACTAMASE (Blac)

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APPLICATION of STRUCTURE ACTIVITY RELATIONSHIPS of the MYCOBACTERIUM TUBERCULOSIS BETA-LACTAMASE (Blac) APPLICATION OF STRUCTURE ACTIVITY RELATIONSHIPS OF THE MYCOBACTERIUM TUBERCULOSIS BETA-LACTAMASE (BlaC) AND THE NEW DELHI METALLO-BETA-LACTAMASE (NDM-1) TO COMBATING BETA- LACTAMASE MEDIATED DRUG RESISTANCE A Dissertation by JOSEPH ANDREW MIRE 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 Chair of Committee, James C. Sacchettini Co-Chair of Committee, Pingwei Li Committee Members, David O. Peterson David H. Russell Head of Department, Gregory D. Reinhart August 2013 Major Subject: Biochemistry Copyright 2013 Joseph Andrew Mire ABSTRACT β-lactamase enzymes catalyze the irreversible hydrolysis of the four-membered cyclic amide ring characteristic of β-lactam antibiotics rendering them inactive and useless against pathogenic bacteria. Understanding structure activity relationships between β-lactam antibiotics and β-lactamases is important for designing novel β- lactams, β-lactamase inhibitors, and β-lactam-based fluorescent probes for rapid diagnosis of β-lactam antibiotic resistant infections. The first half of this study focuses on the class A β-lactamase BlaC from Mycobacterium tuberculosis (Mtb) and addresses intermolecular interactions between BlaC and substrates, inhibitors, and biosensors that influence their kinetic parameters with BlaC and activities against Mtb. The substrate structure activity relationship explained the molecular basis for differential innate resistance of Mtb to faropenem, biapenem, and tebipenem by showing the interactions between BlaC and the lactams that govern differential acyl-intermediate stability and affinity. The inhibitor structure activity relationship revealed features of the BlaC active site that can be exploited to enhance binding and inhibition of BlaC by benzoxaboroles, and demonstrates their utility as potentiators of β-lactam antibiotic activity against Mtb. BlaC-specific β-lactam based fluorescent probes were designed and optimized for Mtb detection. Their utility was demonstrated by detecting down to 10 colony forming units of bacillus Mycobacterium bovis Calmette–Guérin (BCG) in human sputum. ii The second half of this study focuses on the New Delhi Metallo-β-lactamase-1 (NDM-1), which is rapidly generating bacterial resistance to nearly all β-lactams. The NDM-1 gene encodes a class B1 metallo-β-lactamase enzyme. Purified recombinant NDM-1 was biochemically and biophysically characterized. The crystal structures of apo and monometalated NDM-1 provided structural insight into metal binding and the promiscuous enzymatic activity of NDM-1. Mechanistic details of the NMD-1 reaction were examined by comparing crystal structures of NDM-1 in complex with an unhydrolyzed β-lactam substrate and with hydrolyzed products. These structures were used for quantum mechanics / molecular mechanics simulations to estimate the free energy along the β-lactamase reaction coordinate. The results suggest that NDM-1 uses bulk water as the nucleophile that attacks the β-lactam ring, and a coordinated hydroxide ion or water molecule as the catalytic base depending on pH. iii DEDICATION I would like to dedicate this work to my mother and father for their unending love and support throughout my life. iv ACKNOWLEDGEMENTS I would like to thank my committee chair Dr. Sacchettini for giving me the opportunity to conduct this research, and my committee members Dr. Russell, Dr. Li and Dr. Peterson as well as my graduate advisor, Pat Swigert, for their support over the years. I would also like to thank my collaborators: Dickon Alley with Anacor Pharmaceuticals for providing the benzoxaborole molecules, Dr. Eric Rubin and Dr. Noman Siddiqi of Harvard School of Public Health, Dr. David Russell of Texas A&M University, Dr. Jeff Cirillo of Texas A&M Health Science Center, Dr. Jainghong Rao of Stanford University School of Medicine, Dr. Andrzej Joachimiak and the Midwest Center for Structural Genomics, and Dr. Mark Cunningham of University of Texas Pan- American. It has been an honor to work with you all. Chapter 4 is reprinted with permission from Nature Publishing Group, Copyright 2012. Joseph Mire performed the crystallization and structural studies, analyzed the data, and co-wrote the paper. Chapter 5 is reprinted with permission from the Public Library of Science, Copyright 2011. Joseph Mire performed and analyzed the biochemical data and co-wrote the paper. Chapter 6 is reprinted with permission from the Federation of American Societies for Experimental Biology, Copyright 2013. Joseph Mire performed and analyzed the biochemical data and co-wrote the paper. I would like to thank the members of the Midwest Center for Structural Genomics and the Structural Biology Center at Argonne National Laboratory for their v support, specifically Robert Jedrzejczak for cloning the truncated NDM-1 gene. This research has been funded in part by a grant from the U.S. National Institutes of Health GM094585 (A.J.), GM094568 (J.S.), and by the U.S. Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357. Dr. Mark Cunningham has also received support through the National Science Foundation’s FaST program (HRD-0703584), administered by the Department of Educational Programs at Argonne National Laboratory. I would like to thank the Texas Advanced Computing Center (TACC; http://www.tacc.utexas.edu) at the University of Texas at Austin for providing HPC resources that have contributed to the research results reported. Additional computational resources were provided by the HiPAC cluster at the University of Texas–Pan American. Thanks to Gekleng Chhor for proofreading of the NDM-1 manuscript. The atomic coordinates and structure factors have been deposited to the Protein Data Bank (PDB IDs: 4H0D, 4HL2, 4HL1, 4HKY; http://www.pdb.org). Last but not least, thank you to all of my friends and family members for your constant support and encouragement. vi TABLE OF CONTENTS ABSTRACT .......................................................................................................................ii DEDICATION .................................................................................................................. iv ACKNOWLEDGEMENTS ............................................................................................... v TABLE OF CONTENTS .................................................................................................vii LIST OF FIGURES ......................................................................................................... ix LIST OF TABLES ............................................................................................................ xi CHAPTER I INTRODUCTION AND LITERATURE REVIEW .................................. 1 CHAPTER II STRUCTURAL AND FUNCTIONAL INSIGHTS INTO DIFFERENTIAL RESISTANCE OF MYCOBACTERIUM TUBERCULOSIS TO BETA-LACTAMS FAROPENEM, BIAPENEM, AND TEBIPENEM BY BlaC ......... 21 Overview .............................................................................................................. 21 Introduction .......................................................................................................... 22 Results .................................................................................................................. 24 Discussion ............................................................................................................ 36 Materials and Methods ......................................................................................... 43 CHAPTER III STRUCTURAL BASIS FOR POTENTIATION OF BETA- LACTAM ANTIBIOTIC ACTIVITY ON MYCOBACTERIUM TUBERCULOSIS BY BENZOXABOROLES: INHIBITION OF BlaC ............................................................. 47 Overview .............................................................................................................. 47 Introduction .......................................................................................................... 48 Results .................................................................................................................. 50 Discussion ............................................................................................................ 57 Materials and Methods ......................................................................................... 62 CHAPTER IV RAPID POINT-OF-CARE DETECTION OF THE TUBERCULOSIS PATHOGEN USING A BlaC-SPECIFIC FLUOROGENIC PROBE ............................................................................................................................. 65 Overview .............................................................................................................. 65 Introduction .......................................................................................................... 66 Results .................................................................................................................. 68 vii Discussion ............................................................................................................ 82 Materials and Methods ......................................................................................... 85 CHAPTER V STRUCTURE OF APO AND MONOMETALATED FORMS OF NDM-1, A HIGHLY POTENT CARBAPENEM-HYDROLYZING METALLO- BETA-LACTAMASE ...................................................................................................... 89 Overview .............................................................................................................
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