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CARBAPENEMASE PRODUCING Enterobacteriaceae: MOLECULAR EPIDEMIOLOGY and ASSESSMENT of ALTERNATIVE THERAPEUTIC OPTIONS

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CARBAPENEMASE PRODUCING Enterobacteriaceae: MOLECULAR EPIDEMIOLOGY and ASSESSMENT of ALTERNATIVE THERAPEUTIC OPTIONS CARBAPENEMASE PRODUCING Enterobacteriaceae: MOLECULAR EPIDEMIOLOGY AND ASSESSMENT OF ALTERNATIVE THERAPEUTIC OPTIONS By LAURA JIMENA ROJAS COY Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Microbiology and Molecular Biology CASE WESTERN RESERVE UNIVERSITY May, 2018 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Laura Jimena Rojas Coy candidate for the degree of Doctor of Philosophy*. Committee Chair Dr. Arne Riestch Committee Member Dr. Liem Nguyen Committee Member Dr. Anthony Wynshaw-Boris Committee Member Dr. Robert A. Bonomo Date of Defense March 22, 2018 *We also certify that written approval has been obtained for any proprietary material contained therein. DEDICATION To my mother Maria Grelly and my father Daniel for raising me believing that with hard work I could achieve anything I set my mind to. To my loving brother Cami for constantly looking up to me, inspiring me to always do my best; and finally to my adorable little sister Angie for her infinite an unconditional love. I love you all so much. iii ACKNOWLEDGEMENTS My deepest gratitude and appreciation to my mentor, Dr. Robert A. Bonomo, for being so generous, understanding and patient and for giving me so many wonderful opportunities, in spite of not following the "traditional" path. In addition to the tremendous academic support, he has shown me by his example that humbleness, fairness and leadership is what truly makes a good scientist. To my committee members thank you for your valuable suggestions and criticisms. To everyone in the Bonomo Lab, thank you for sharing your expertise with me and, for constantly helping me, and for each and every one of your invaluable contributions to the work summarized in this dissertation. Special thanks to Steve Marshall, Sue Rudin, Magdalena Taracila, Dr. Melissa Barnes and Dr. Krisztina Papp-Wallace, you helped me in more ways than one and I will always be very grateful. My most sincere gratitude to Drs. George and Erica Weinstock for hosting me in their lab. I am very grateful with you and all the lab members not only for all the knowledge shared, but also for always making me feel at home. Special thanks to Blake Hanson, Joe Brown and Dan Phillips. I would like to extend thanks to all the collaborators, who so generously contributed to the work presented in this dissertation; I am grateful to all of those with whom I have had the pleasure to work with. iv I would also like to express my gratitude to Fulbright for supporting my Doctoral studies, and to Josaba Uribe at LASPAU for all her help along the process. Profound gratitude goes to Dr. Maria Virginia Villegas and Dr. Cesar Arias for their continuous mentorship and encouragement, and most importantly for constantly having faith in my work and potential, without you this journey would not have even begun. Finally, my most heart-felt thanks to all the friends I’ve met along this journey Michal Bonar, Nilmarie Ayala, Liang Zhu, Roberto Viau, Larry Bodnar, Magda Taracila, Melissa Barnes, and specially to those who through the years have become like family: Federico Perez, Sory Ruiz, Isabel Blanco, Elsa De La Cadena. Lastly, to my best friend, roommate and adventure partner, Mafe Mojica: thanks for always encouraging me, and for your emotional, scientific, and all kinds of support along the way, I could not have done it without you. v TABLE OF CONTENTS CHAPTER 1 - INTRODUCTION 1 Β-LACTAMS AND Β-LACTAM RESISTANCE MECHANISMS ......................................... 1 DISSEMINATION OF ANTIMICROBIAL RESISTANCE ............................................... 3 IMPACT OF CARBAPENEM RESISTANT ENTEROBACTERIACEAE, THE IMPORTANCE OF CARBAPENEMASES AND THE THREAT TO Β-LACTAM THERAPY IN THE WORLD ............ 7 Klebsiella pneumoniae CARBAPENEMASE (KPC): A MAJOR THREAT WORLDWIDE ...... 10 NEW DELHI METALLO- β-LACTAMASE, AN EMERGING MBL ..................................... 13 OXA-48: “THE PHANTOM MENACE” ..................................................................... 16 Β-LACTAM INHIBITORS ................................................................................ 20 COLISTIN AS A LAST RESORT ANTIBIOTIC FOR CARBAPENEM RESISTANT ENTEROBACTERIACEAE ................................................................................ 26 COLISTIN MODE OF ACTION AND RESISTANCE IN CARBAPENEM RESISTANT K. pneumoniae ................................................................................................... 27 CHROMOSOMALLY MEDIATED COLISTIN/POLYMYXIN RESISTANCE ............................. 28 CHAPTER 2 - BORONIC ACID TRANSITION STATE INHIBITORS AS AN ALTERNATIVE FOR CLASS A BETA-LACTAMASES ................................... 61 INTRODUCTION .......................................................................................... 61 MATERIALS AND METHODS ........................................................................... 65 SYNTHESIS ...................................................................................................... 65 BACTERIAL STRAINS AND PLASMIDS ..................................................................... 65 β-LACTAMASE PURIFICATION .............................................................................. 65 STEADY-STATE KINETICS .................................................................................... 66 vi ANTIMICROBIAL SUSCEPTIBILITY TESTING ............................................................. 68 MOLECULAR MODELING-DOCKING ...................................................................... 69 RESULTS AND DISCUSSION ................................................................................ 70 SAR OF BATSIS AGAINST KPC-2 AND SHV-1 β-LACTAMASES AND MOLECULAR MODELING. ...................................................................................................... 70 SUSCEPTIBILITY TESTING AND BIOCHEMICAL ANALYSIS OF COMPOUND 2B. ................. 74 CONCLUSION ................................................................................................... 76 CHAPTER 3 - NDM & OXA-48, EMERGING CARBAPENEMASES ................ 88 INITIAL ASSESSMENT OF THE MOLECULAR EPIDEMIOLOGY OF blaNDM-1 IN COLOMBIA ............................................................................................................... 89 METHODS ....................................................................................................... 90 RESULTS AND DISCUSSION ................................................................................. 91 NDM-5 AND OXA-181 β-LACTAMASES: A SIGNIFICANT THREAT CONTINUE TO SPREAD IN THE AMERICAS ....................................................................................... 97 CONCLUSION ................................................................................................. 103 CHAPTER 4 - AN ANALYSIS OF THE EPIDEMIC OF KPC-PRODUCING Klebsiella pneumoniae: CONVERGENCE OF TWO EVOLUTIONARY MECHANISMS CREATES THE "PERFECT STORM” ................................. 116 INTRODUCTION ........................................................................................ 116 METHODS ............................................................................................... 117 STRAIN SELECTION. ........................................................................................ 118 DNA PREPARATION, LIBRARY CONSTRUCTION, SEQUENCING, ASSEMBLY AND ANNOTATION. ................................................................................................. 118 vii IN SILICO MLST ANALYSIS, IDENTIFICATION OF ANTIMICROBIAL RESISTANCE DETERMINANTS, VIRULENCE FACTORS PLASMID TYPING AND CAPSULAR TYPING. ........ 119 PHYLOGENETIC ANALYSES ............................................................................... 120 RESULTS ................................................................................................ 121 DISCUSSION ............................................................................................ 125 CONCLUSION ........................................................................................... 130 CHAPTER 5 - COLISTIN RESISTANCE IN CARBAPENEM-RESISTANT Klebsiella pneumoniae: LABORATORY DETECTION AND IMPACT ON MORTALITY .......................................................................................... 158 INTRODUCTION ........................................................................................ 158 METHODS ............................................................................................... 159 PATIENTS ...................................................................................................... 159 MICROBIOLOGY .............................................................................................. 159 CLINICAL DATA ............................................................................................... 161 STATISTICS .................................................................................................... 162 RESULTS ................................................................................................ 162 COLISTIN SUSCEPTIBILITY TESTING .................................................................... 162 CLINICAL CHARACTERISTICS ............................................................................. 163 PREVIOUS ANTIBIOTIC EXPOSURE ..................................................................... 164 MICROBIOLOGY .............................................................................................. 165 TREATMENT AND MORTALITY
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