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Discovery, Characterization and Structural Studies of Inhibitors Against Mycobacterium Tuberculosis Adenosine Kinase and Biotin

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Discovery, Characterization and Structural Studies of Inhibitors Against Mycobacterium Tuberculosis Adenosine Kinase and Biotin DISCOVERY, CHARACTERIZATION AND STRUCTURAL STUDIES OF INHIBITORS AGAINST MYCOBACTERIUM TUBERCULOSIS ADENOSINE KINASE AND BIOTIN PROTEIN LIGASE A Dissertation by ROBERTO A. CRESPO MORALES Submitted to the Office of Graduate and Professional 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 Committee Members, Jean-Philippe Pellois David Peterson Tadhg Begley Head of Department, Gregory Reinhart December 2017 Major Subject: Biochemistry Copyright 2017 Roberto A. Crespo Morales ABSTRACT The rapid emergence of drug-resistant Mycobacterium tuberculosis (Mtb) coupled to the high incidence of HIV-Mtb coinfection is of global concern. Consequently, there is a worldwide necessity to develop new drugs with novel mechanisms of action and new molecular targets. In this dissertation, we describe a crystallographic and high-throughput screening (HTS) approach towards the identification and structural characterization of inhibitors against Mycobacterium tuberculosis adenosine kinase (MtbAdoK) and biotin protein ligase (MtbBpL). Parallel studies were also performed to evaluate the in vitro potency and antimycobacterial profile of the compounds. Finally, X-ray crystallography was employed to investigate the structural basis of inhibition and to perform structure- guided drug design. In the first study, we focused on the biochemical, chemical synthesis and structural characterization of adenosine analogs as inhibitors of MtbAdoK. Here, we adopted a bottom-up structural approach towards the discovery, design, and synthesis of a series of compounds that displayed inhibitory constants ranging from 4.3-121.0 nM against the enzyme. Two of these compounds exhibited low micromolar activity against Mtb with 50.0 % minimum inhibitory concentrations of 1.7 and 4.0 µM. Our selectivity studies showed that the compounds display a higher degree of specificity of MtbAdoK when compared to the human enzyme (hAdoK). Finally, our crystallographic studies revealed ii the presence of a potentially therapeutically relevant cavity that is unique to the MtbAdoK homodimer. Next, we describe the discovery, biochemical and structural characterization of novel dihydro spiro compounds as inhibitors of MtbAdoK. Here, we utilized an HTS approach for the identification of the aforementioned compounds. Our enzymatic assays showed that the compounds are selective inhibitors of MtbAdoK when compared hAdoK. In addition, our antimycobacterial studies revealed that the compounds possess nanomolar potency against Mtb (500.0-810.0 nM). Finally, the crystallographic studies revealed that the inhibitors bind in a previously unknown pocket within the enzyme. Lastly, we explore the potential of MtbBpL as a drug target. Following identification of the compounds via HTS screening, we demonstrate that the inhibitors lacked any activity against human dermal fibroblast but possess antimycobacterial properties. Finally, steady-state kinetic experiments revealed that the compounds are noncompetitive inhibitors of the enzyme suggesting the presence of a previously uncharacterized allosteric site. iii ACKNOWLEDGEMENTS I would like to express my gratitude to my graduate advisor, Dr. James C. Sacchettini, and my committee members, Dr. Pellois, Dr. Peterson and Dr. Begley, for their guidance and support throughout the course of this research. I would also like to acknowledge the Sacchettini Lab members (past and present) from which I collectively learned everything I know today. Thanks also go to my friends and colleagues and the department faculty and staff for making my time at Texas A&M University a great experience. Finally, and most importantly thanks to my mother, father and siblings for their unconditional support and encouragement throughout graduate school and for always pushing me forward to strive for success. iv CONTRIBUTORS AND FUNDING SOURCES Contributors Part 1, faculty committee recognition This work was supervised by a dissertation committee consisting of graduate advisor Professor James C. Sacchettini, Professors Jean-Philippe Pellois and David Peterson of the Department of Biochemistry and Biophysics and Professor Tadhg Begley of the Department of Chemistry. Part 2, student/collaborator contributions The work described in section 2 is the product of a collaboration between Merck Research Laboratories (MRL) and the Sacchettini Research Group (TAMU). Synthesis of the nucleoside analogs of was carried out by Merck Research Laboratories and WuXi AppTec. Dr. Qun Dang, a former employee of MRL (now Lilly) and Dr. Takao Suzuki of WuXi AppTec wrote the medicinal chemistry aspects of the paper and supplementary information. All other work not related to medicinal chemistry including enzymatic characterization, antimycobacterial profiling, co-crystallization, crystallographic data acquisition and analysis, manuscript and supplementary information preparation was carried out by the student. All of the work performed on sections 3, and 4 was conducted by the student, including enzymatic characterization, antimycobacterial testing, co-crystallization of compounds, crystallographic data acquisition and analysis, manuscript and supplementary v information preparation. Finally, in all cases, X-ray crystallographic data for sections 2, 3 and 4 were collected at the Argonne National Laboratory, beamlines 19ID, 19BM, and 23ID and whole cell testing of compounds against human dermal fibroblast cells were carried out by Dr. Kim Loesch and Ms. Wen Dong from the Sacchettini Research Group. Funding Sources All the work performed in the Sacchettini Lab was made possible by funding from the Welch Foundation (A0015), NIH (P01AI095208) and the Bill and Melinda Gates Foundation (OPP1024055). The work carried out by Merck Research Laboratories and WuXi AppTec was privately funded by Merck Research Laboratories. vi TABLE OF CONTENTS Page ABSTRACT .......................................................................................................................ii ACKNOWLEDGEMENTS .............................................................................................. iv CONTRIBUTORS AND FUNDING SOURCES .............................................................. v TABLE OF CONTENTS .................................................................................................vii LIST OF FIGURES ............................................................................................................ x LIST OF TABLES .......................................................................................................... xiv 1. INTRODUCTION .......................................................................................................... 1 1.1 History of tuberculosis ............................................................................................. 1 1.2 Global burden of tuberculosis .................................................................................. 5 1.2.1 Rise of drug-resistant Mtb ................................................................................. 7 1.2.2 Multidrug-resistant and extensively drug-resistant Mtb ................................. 10 1.2.3 Totally drug-resistant Mtb ............................................................................... 13 1.3 Tuberculosis control and treatment: first-line, second-line, and add-on drugs ...... 13 1.3.1 Drug-susceptible Mtb treatment: first-line drugs ............................................ 15 1.3.2 MDR, XDR and TDR Mtb treatment: second-line and add-on drugs............. 29 1.4 Strategies for drug discovery against drug-resistant bacteria ................................. 46 1.4.1 The ideal Mtb drug target ................................................................................ 46 1.4.2 Target-based drug discovery approaches to identify new drugs ..................... 49 1.4.3 Phenotypic-based drug discovery approaches to identify new drug targets ... 52 1.4.4 Repurposing and screening of previously approved drugs ............................. 54 1.4.5 Tuberculosis structural genomics consortium: a worldwide collaboration towards the identification and characterization of new drug targets for Mtb drug development ............................................................................................................. 55 2. STRUCTURE-GUIDED DESIGN OF 6-SUBSTITUTED ADENOSINE ANALOGS AS POTENT INHIBITORS OF MYCOBACTERIUM TUBERCULOSIS ADENOSINE KINASE ................................................................................................... 58 vii 2.1 Background and significance ................................................................................. 58 2.2 Materials and methods ........................................................................................... 62 2.2.1 Cloning, expression and purification of recombinant MtbAdoK and hAdoK 62 2.2.2 Enzymatic assay, IC50 determination, steady-state kinetics and Ki determination ............................................................................................................ 63 2.2.3 Crystallization, data collection, and crystal structure determination .............. 65 2.2.4 Antimycobacterial assay .................................................................................. 66 2.2.5 Human dermal fibroblast cytotoxicity assay ................................................... 67 2.3 Results and discussion ...........................................................................................
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