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Phd Thesis Antibiotic Drug Discovery UNIVERSITY OF COPENH A G E N DEPARTMENT OF BIOLOG Y PhD thesis Rasmus Nielsen Klitgaard, M.Sc. Antibiotic Drug Discovery Potentiation of the quinolones and targeting the initiation of DNA replication This thesis has been submitted to the PhD School of The Faculty of Science, University of Copenhagen, Denmark, 28. February 2018. Academic advisor Anders Løbner-Olesen Department of Biology Functional Genomics University of Copenhagen, Denmark. Assessment committee Dan Andersson Department of Medical Biochemistry and Microbiology University of Uppsala, Sweden. Mogens Kilstrup Department of Biochemistry and Biomedicine Metabolic Signaling and Regulation Danish Technical University, Denmark. Signe Lo Svenningsen Department of Biology Biomolecular Sciences University of Copenhagen, Denmark. Submitted: 28.02.2018 1 Acknowledgements First, I would like to thank my supervisor Anders Løbner-Olesen for his excellent support and guidance throughout my PhD. I have highly appreciated that Anders has been available more or less every day and gladly discussed any questions I might have had. I would also like to thank Godefroid Charbon, not only for our collaboration on paper II presented in this thesis, but also for always taking time to discuss and give advice on my other projects. It has been greatly cherished. Furthermore, I would like to thank the staff at Naicons srl. and all of the people who have been part of the ALO lab: Thomas T. Thomsen, Jakob Frimodt-Møller, Maria S. Haugan, Christoffer Campion, Anna E. Ebbensgard, Michaela Lederer, Henrik Jakobsen, Leise Riber and Belén M. Chamizo. A thanks, should also be given to my bachelor student, Anne Kristine Schack, who contributed to the construction of the screening system presented in paper III. Finally, I would like to thank my girlfriend, Marie, my family and my friends for their great support and interest in my work. 2 Abstract – English Antibiotic resistance has been deemed as one of the biggest threats to the global public health by the World health Organization. In 2050, an estimated 10 million deaths per year will be attributed to antimicrobial resistance, thus proper action needs to be taken to stop this negative development. An important mean in the arms race against antibiotic resistance is the discovery and development of novel antibiotics, but also preserving the efficacy of the antibiotics that are already in clinical use. In paper I, we search for ciprofloxacin helper drug targets in an effort to preserve the use of this widely applied antibiotic. Using a combined genetic and transcriptomic approach, the AcrAB-TolC efflux pump and the SOS response genes, RecA and RecC, are identified as potential targets for helper drugs in Escherichia coli strains with low-level ciprofloxacin resistance. In addition, our results also indicate that reversing high-level ciprofloxacin resistance is likely not plausible. In paper II, we present two novel cell based screens for identifying inhibitors of the chromosomal DNA replication initiation in bacteria. The screens are based on growth rescue of cells that rigorously over-initiate the DNA replication, due to either increased regeneration of the active ATP bound form of the replication initiator protein DnaA, or by being deficient in the process known as regulatory inactivation of DnaA (RIDA). Screening a library of 400 microbial extracts, revealed the iron chelator deferoxamine as a compound that rescues the growth of over-initiating cells. Albeit not by decreasing the replication initiation frequency, but by reducing the production of reactive oxygen species. Substantiating the model that oxidative DNA damage and its repair promotes the lethal action of hyper-replication. In paper III, we constructed and verified a novel high throughput, cell based, fluorescence screen for inhibitors of chromosome replication initiation in bacteria. The screen utilizes an E. coli mutant that is resistant to replication initiation inhibitors and holds a fluorescence reporter system for DNA replication inhibitors. This screen was also subjected to the above-mentioned library of microbial extracts, though it did not lead to any positive hits. 3 Abstract – Danish Verdens Sundheds organisationen, WHO, har udnævnt antibiotika resistens til at være en af de største trusler mod det globale sundhedssystem. Det er blevet estimeret at i 2050 vil ca. 10 millioner dødsfald årligt være associeret med antibiotika resistens. Det er derfor yderst vigtigt at der allerede nu tages de nødvendige initiativer til at begrænse denne negative udvikling. En af de væsentligste faktorer i kampen mod antibiotika resistens er udviklingen af nye antibiotika, samt at præservere virkningen af de antibiotika som allerede bruges i klinikken. I et forsøg på at præservere den kliniske anvendelighed af det ofte benyttede antibiotika ciprofloxacin. Søger vi i artikel I efter gener i Escherichia coli hvis deletion reverserer ciprofloxacin resistens og dermed kan bruges som mål for ciprofloxacin hjælpestoffer. Ved hjælp af genetisk deletions analyse identificerede vi efflux pumpen, AcrAB-tolC, samt SOS-respons proteinerne, RecA og RecC som mulige mål for ciprofloxacin hjælpestoffer i lav-resistente stammer af E. coli. Ydermere viste vores resultater også at det formentlig ikke er muligt at reverserer ciprofloxacin resistens i høj-resistente stammer af E. coli. I artikel II præsenterer vi to nye screeningssystemer til at identificere inhibitorer af initieringen af kromosomal DNA replikation i bakterier. Disse to screeningssystemer er baseret på celler der over-initierer DNA replikationen, via henholdsvis forhøjet regenerering af den ATP bundne form af initieringsproteinet DnaA eller mangel på processen kendt som regulativ inaktivering af DnaA (RIDA). Denne over-initiering er lethal for cellerne. Under screening af et bibliotek bestående af 400 mikrobielle ekstrakter, identificerede vi jern chelatoren deferoxamine, som et stof der kan redde væksten af celler der over-initierer replikationen. Dog ikke ved at nedsætte initierings frekvensen, men ved at reducere produktionen af reaktive oxygen radikaler. Hvilket ydermere fast slår modellen, at oxidativ DNA skade og dets reparation medierer celledød i bakterier det over-initierer DNA replikationen. I artikel III konstruerede og verificerede vi endnu et nyt screeningssystem til inhibitorer af DNA replikations initieringsprocessen. Denne screen består af en E. coli mutant der er resistent over for stoffer der blokerer replikations initierings processen og samtidig indeholder et fluorescens baseret reporter system der aktiveres af replikations initierings inhibitorer. Denne screen blev også testet mod det ovennævnte bibliotek af mikrobielle ekstrakter, men gav ingen positive hits. 4 List of papers Paper I Can Ciprofloxacin Resistance be Reversed by Helper Drugs? Rasmus N. Klitgaard, Bimal Jana, Luca Guardabassi, Karen Leth Nielsen and Anders Løbner-Olesen. Paper II A strategy for finding DNA replication inhibitors in E. coli identifies iron chelators as molecules that promote survival of hyper-replicating cells. Godefroid Charbon, Rasmus Nielsen Klitgaard, Charlotte Dahlmann Liboriussen, Peter Waaben Thulstrup, Sonia Ilaria Maffioli, Stefano Donadio and Anders Løbner-Olesen. Paper III A Novel Fluorescence Based Screen for Inhibitors of the Initiation of DNA Replication in Bacteria. Rasmus N. Klitgaard and Anders Løbner-Olesen. Papers not included in the thesis Ciprofloxacin intercalated in fluorohectorite clay: Identical pure drug activity and toxicity with higher adsorption and controlled release rate. E. C. dos Santos, Z. Rozynek, E. L. Hansen, R. Hartmann-Petersen, R. N. Klitgaard, A. Løbner-Olesen, d L. Michels, A. Mikkelsen, T. S. Plivelic, H. N. Bordallo and J. O. Fossum. Mutations in the Bacterial Ribosomal Protein L3 and Their Association with Antibiotic Resistance. Rasmus N. Klitgaard, Eleni Ntokou, Katrine Nørgaard, Daniel Biltoft, Lykke H. Hansen, Nicolai M. Trædholm, Jacob Kongsted, Birte Vester. 5 Table of contents ACKNOWLEDGEMENTS ................................................................................................... 2 ABSTRACT – ENGLISH ..................................................................................................... 3 ABSTRACT – DANISH ....................................................................................................... 4 LIST OF PAPERS ............................................................................................................... 5 TABLE OF CONTENTS ...................................................................................................... 6 A BRIEF HISTORY OF ANTIBIOTICS ................................................................................ 9 The early days ................................................................................................................................................................... 9 The golden age of antibiotics ........................................................................................................................................... 9 The present and future of antibiotics ............................................................................................................................ 10 PART I: POTENTIATION OF THE QUINOLONES ........................................................... 11 Discovery and development of the quinolones ............................................................................................................. 11 The quinolone targets ....................................................................................................................................................
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