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Design and Synthesis of Metallo-Β-Lactamase Inhibitors

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Design and Synthesis of Metallo-Β-Lactamase Inhibitors Design and synthesis of metallo-β-lactamase inhibitors Ricky Michael Cain Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Chemistry July 2015 - ii - The candidate confirms that the work submitted is his own, except where work which has formed part of jointly-authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. Chapter 4 contains work described in the publication ‘Applications of structure-based design to antibacterial drug discovery’, as published in the journal, Bio-organic Chemistry. The candidate carried out the literature review and manuscript preparation with S. Narramore. The candidate also conducted all work relating to metallo-β-lactamase inhibitor discovery. M. McPhillie and K. Simmons provided information on triclosan derivative and DHODH respectively, and C. Fishwick helped with manuscript preparation. Chapter 8 contains work described in the publication ‘Assay Platform for Clinically Relevant Metallo-β-lactamases’, as published in the journal, Journal of Medicinal Chemistry. The candidate contributed in silico studies, S. van Berkel, J. Brem and A. Rydzik carried out biological evaluation, R.Salimraj, A. Verma and R. Owens expressed the relevant proteins., and C. Fishwick, J. Spencer and C. Schofield prepared the manuscript. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Ricky Michael Cain to be identified as Author of this work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. © 2015 The University of Leeds and Ricky Michael Cain - iii - Acknowledgements I would like to express my thanks to the following people for their support and guidance throughout my research and during preparation of this thesis. I would like to thank my supervisor Professor Colin Fishwick for giving me the opportunity to work on this project and his continued guidance and support throughout. The Medical Research Council for funding my research. The Fishwick research group particually Dr. Katie Simmons, Dr. Martin McPhillie, Dr. Fraser Cunningham, Sarah Narramore, Ryan Gonciraz, James Gorden and Lewis Turner who have made the last few years thoroughly enjoyable. Biological collaborators: Dr Jϋrgen Brem and Professor Chris Schofield at the University of Oxford (Enzymatic assays). Dr James Spencer at the University of Bristol. (MIC determination). My former MChem students: Joshua Meyers and Rachel Johnson The School of Chemistry technical staff: Simon Barrett (NMR service), Ian Blakeley (Elemental analysis & NMR service), Martin Huscroft (HPLC service), and Tanya Marinko-Covell (Mass spectrometry service & Elemental analysis). My family who have loved and supported me throughout my education. Finally, to my girlfriend Hayley for putting up with me and the many lost evenings and weekends while I produced this thesis. - iv - Abstract Bacterial resistance is a continuously evolving threat to our most common antibiotics; the β-lactams. Most recently, the production of β-lactamase enzymes by bacteria rendered many of our current antibiotics unusable threatening to plunge us into a ‘pre-antibiotic’ era. Metallo-β-lactamases (MBLs) play a key role in bacterial resistance to β-lactam antibiotics by efficiently catalysing the hydrolysis of the β-lactam amide bond. Since their discovery, the clinically relevant MBLs, Verona integrin-encoded metallo-β- lactamase (VIM-2), Imipenemase (IMP-1), New Delhi metallo-β-lactamase (NDM-1) and Sao Paulo metallo-β-lactamase (SPM-1), have spread across the world with cases reported in almost all countries. This thesis describes a number of approaches to the identification of inhibitors of MBLs. A combination of structure-based drug design, chemical synthesis and biological evaluation has been used to rationally identify novel inhibitors of VIM-2, IMP-1, NDM-1 and SPM-1 which have also been co administered with a current β-lactam antibiotic and been found to re- sensitise the bacteria to the antibiotic. Four novel classes of inhibitor have been investigated by taking different approaches to inhibitor discovery. A vHTS screening campaign was conducted to identify potential inhibitors from libraries of known compounds. The campaign identified some weak binding inhibitors. Boronic acid-based inhibitors were identified by using vHTS and de novo design respectively and were synthesised which gave IC50’s in the region of 10 nM against VIM-2 and NDM-1. Additionally, a new computational method for the identification of peptides which bind to enzymes has been developed which found Pro-Cys-Phe to be the most active peptide for binding to NDM-1 with an IC50 of 183 µM. This method could be applied to many other systems. In the final approach, de novo design using SPROUT led to the design of a novel thiol based inhibitor class. The inhibitor class has been co-crystallised in VIM-2 and gives IC50 values in the range of 200 nM. The inhibitor class has also successfully shown a 100 fold recovery of the MIC of meropenem against NDM-1 expressing bacteria. - v - Table of Contents Acknowledgements .................................................................................... iii Abstract ....................................................................................................... iv Table of Contents ........................................................................................ v List of Abbreviations and Symbols ........................................................ viii Amino Acids ............................................................................................... xi Chapter 1 Bacterial Resistance .................................................................. 2 1.1 The structure of bacteria ............................................................... 3 1.2 Antibacterial agents ....................................................................... 6 1.3 Bacterial resistance ..................................................................... 13 Chapter 2 β-lactamases ............................................................................ 17 2.1 Serine-β-lactamases ..................................................................... 18 2.2 Metallo-β-lactamases (MBLs) ........................................................ 22 2.3 New Delhi metallo-β-lactamase 1 (NDM-1) ................................... 25 2.4 The other clinically relevant MBLs ................................................. 30 2.5 Inhibitors of MBLs.......................................................................... 35 Chapter 3 Project goals ............................................................................ 40 3.1 Molecular design stage ................................................................. 40 3.2 Chemical synthesis ....................................................................... 40 3.3 Biological evaluation...................................................................... 40 Chapter 4 Application of vHTS to inhibitor discovery.84 ........................ 44 4.1 Docking programs ......................................................................... 45 4.2 Program choice ............................................................................. 48 4.3 Protocol for vHTS screening using AutoDock ............................... 50 4.4 Molecular docking of the Peakdale Molecular screening collection ..................................................................................... 52 4.5 Molecular docking of the Chembridge screening collection ........... 61 4.6 Conclusions ................................................................................... 62 Chapter 5 Boronic acid inhibitors ............................................................ 64 5.1 Known boron-containing drugs ...................................................... 66 5.2 Boron containing β-lactamase inhibitors ....................................... 67 5.3 Targeting the MBLs with boron-containing inhibitors ..................... 69 5.5 Synthetic route development ......................................................... 76 5.6 Biological evaluation...................................................................... 82 - vi - 5.7 Conclusions ................................................................................... 83 Chapter 6 Cysteine-containing peptides ................................................. 85 6.1 Methods of identifying the active peptides ..................................... 85 6.2 Peptides as inhibitors of MBLs ...................................................... 87 6.3 Peptide library generation ............................................................. 89 6.4 Docking protocol ........................................................................... 90 6.5 Docking results .............................................................................. 91 6.6 Biological evaluation...................................................................... 94 6.7 D and DL combination trimers ....................................................... 96 6.8 Peptide mimics .............................................................................. 98 6.9 Conclusions ................................................................................
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