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The Biosynthesis of Cis-Carbapenems and the Development of Penem Antibiotics for the Treatment of Tuberculosis

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The Biosynthesis of Cis-Carbapenems and the Development of Penem Antibiotics for the Treatment of Tuberculosis THE BIOSYNTHESIS OF CIS-CARBAPENEMS AND THE DEVELOPMENT OF PENEM ANTIBIOTICS FOR THE TREATMENT OF TUBERCULOSIS by Evan P. Lloyd A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland February, 2017 © 2017 Evan P. Lloyd All Rights Reserved Abstract Inspired by their naturally occurring members, the carbapenem class of β-lactam antibiotics have been heavily researched over the past forty years, resulting in the development of a set of broad-spectrum, β-lactamase resistant, last resort antibiotics for the treatment of severe bacterial infections. Manufactured by total synthesis, carbapenems are limited to their use in the first world due to their high cost. As antibacterial resistance increases, the need for these drugs is rising. To combat the high price of manufacture, fermentation or semi-synthetic methods that take advantage of the enzymatic machinery of their biosynthesis to assemble the carbapenem core would reduce the number of synthetic steps and ultimately the cost of production. The key biosynthetic steps to assemble the carbapenem core, however, remain unknown. In this dissertation, we studied the MM 4550 biosynthetic gene cluster to examine how carbapenems are made by comparative genomics and we uncovered clues about how cis-carbapenems might diverge from thienamycin. Total syntheses of cis-carbapenems were completed for activity assays with newly discovered enzymes in the MM 4550 gene cluster; CmmSu, Cmm17 and CmmPah. Additionally, 2-thioalkyl carbapenam substrates were synthesized for assays with ThnK in vitro, which was found to perform sequential double methylation of carbapenam substrates for the installation of the 6-ethyl sidechain of thienamycin. The function of ThnK has provided a path forward to uncovering the remaining biosynthetic steps carries out by the function of ThnL and ThnP. In collaboration with Prof. Gyanu Lamichhane at the Johns Hopkins Medical Institute, a new class of cell wall crosslinking transpeptidases in Mycobacteria, L,D- ii transpeptidases (Ldts), was screened for their inhibition by commercially available β- lactam antibiotics using intact protein analysis electrospray ionization high-resolution mass spectrometry. We found that carbapenems form covalent adducts with Ldts and through efficient inhibition are potent drugs against Mycobacterium tuberculosis. Faropenem was found to be the most potent inhibitor of Ldts, however, unlike carbapenems, was unsuccessful against Tuberculosis infection in vivo. As a result, we synthesized new penems that take advantage of the best carbapenem structural features with the goal to retain both the high potency of penems but the in vivo success of carbapenems. Our lead compound has been found to have highly potent antibacterial activity, as evidenced by MIC90 data against M. tuberculosis and other pathogenic bacteria. The results of in vivo tests in an animal model of the disease will be forthcoming. Thesis advisor: Professor Craig A. Townsend, Department of Chemistry Dissertation Committee: Professor John P. Toscano, Department of Chemistry Professor John D. Tovar, Department of Chemistry iii Acknowledgements I have many people to thank for helping me along my journey through graduate school. I must first thank Dr. Craig Townsend. Dr. Townsend has taught me how to study problems with a critical eye. Through his encouragement, I’ve learned how to conduct scientific research at a high level using all the resources at my disposal. I especially thank him for his patience and unwavering support for me in my career. He has always been understanding of my needs scientifically and personally, and I can’t thank him enough for his hard work every day. I’d also like to thank our collaborators, Dr. Gyanu Lamichhane and Dr. Squire Booker. Gyanu has provided me with many opportunities to contribute to his great project, and through collaboration with his lab we have learned a lot about the power of synthetic chemistry for drug discovery. Dr. Booker was so welcoming to us each time visiting his lab and provided us with his expertise and facilities without which we would have never learned anything about ThnK, There is nobody I know other than Dr. Rongfeng Li who has as much knowledge and expertise in biological research. He has helped me throughout my graduate career with a unique perspective. Rongfeng is always excited to talk about research with me and has been a big influence in my education as a chemical biologist. My work with Dr. Daniel Marous on ThnK was my favorite project during my Ph.D. Due to his friendship, I had fun on our trips to Penn State even though those weeks were some of the longest hours I spend in lab. Dr. Kristos Moshos was a very patient mentor when I first joined the lab. Through his guidance I quickly refined my synthetic skills during my summer rotation in 2010, and without his help I wouldn’t have accomplished much in my first few years. iv Dr. Andrew Buller, Dr. Courtney Hastings and Dr. Jesse Li helped mentor me as a scientist and a young professional early in my Ph.D. Darcie Long, Doug Cohen, Ryan Oliver and Jacob Kravitz have become my best friends in the lab, and besides talking at length about science, I appreciate the time I spent with them outside of lab. I also thank the next generation of graduate students, particularly Hunter Batchelder, Erica Sinner and Trevor Zandi who will continue the projects I worked on for so many years. I wish Hunter luck with the cis-carbapenem biosynthesis project, Trevor with the Tuberculosis collaboration, and Erica with the radical SAMs. Their future work will solve the remaining mysteries of carbapenem biosynthesis and generate important new drugs. Without the Johns Hopkins chemistry department staff I wouldn’t be able to conduct the experiments needed to make any of the progress discussed in this dissertation. I thank Dr. Phil Mortimer for keeping the mass spectrometers up and running, and Dr. Cathy Moore, Dr. Joel Tang, Dr. Chuck Long, and Dr. Ananya Majumdar for their help with NMR spectroscopy. As administrative staff, Rosalie Elder, Lauren McGhee, Jean Goodwin and John Kidwell were always generous with providing help when I needed it. Our facilities manager Boris Steinberg works as hard as anyone in the department and his enthusiasm and broad skill set has solved a lot of technical issues needed to keep our work moving forward, from tracking down missing packages to assisting me with using the drill press in the machine shop. Most of all, I have to thank my family. Without my wife Christina, none of the work described here would be possible. She has encouraged me through the frustrating times and celebrated with me every success. I can’t wait to begin the next chapter of my v life with Christina and our son, Darren. My parents and sister, Emma, have always been confident in my abilities even when I wasn’t, and I am grateful that I know I can lean on them whenever necessary. My best friends Spencer and Drew provided much needed relief and relaxation, and their perspective on the world outside of lab keeps me grounded. Nobody can accomplish anything worth achieving without support from their friends, family and coworkers. The best lesson I learned was to never be afraid to ask for help; whether it’s from a fellow student in lab or a professor at a different university. I’ve come to appreciate collaboration with others, and working with people to solve complex problems using our combined experiences and skill sets is my favorite aspect of scientific research. I am fortunate to have worked with all of those listed in the above paragraphs; a few words cannot describe how grateful I am for each person who has influenced my education. vi For Christina “People who work together will win, whether it be against complex football defenses, or the problems of modern society” -Vince Lombardi- vii Publications Drawing Upon This Thesis 1. R. Li, E.P. Lloyd, K.A. Moshos, C.A. Townsend. “Identification and characterization of the carbapenem MM 4550 and its gene cluster in Streptomyces argenteolus ATCC 11009.” ChemBioChem, 2014, 15 (2), 320-31. 2. M.J. Bodner, R.M. Phelan, M.F. Freeman, K.A. Moshos, E.P. Lloyd, C.A. Townsend. “Definition of the common and divergent steps in carbapenem β-lactam antibiotic biosynthesis.” ChemBioChem, 2011, 12 (14), 2159-65. 3. D.R. Marous, E.P. Lloyd, A.R. Buller, T.L. Grove, A.J. Blaszczyk, S.J. Booker, C.A. Townsend. “Consecutive radical S-adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis.” Proc. Natl. Acad. Sci. U.S.A., 2015, 112 (33), 10354-8. 4. L.A. Basta, A Ghosh, Y. Pan, J Jean, E.P. Lloyd, C.A. Townsend, G. Lamichhane, M.A. Bianchet. “Loss of a functionally and structurally distinct L,D-transpeptidase LdtMt5, compromises cell wall integrity in Mycobacterium tuberculosis.” J. Biol. Chem., 2015, 290 (42), 25670-85. 5. P. Kumar, A. Kaushik, E.P. Lloyd, S-G. Li, R. Mattoo, N. Ammerman, D. Bell, A. Perryman, T. Zandi, S. Ekins, S. Ginell, C.A. Townsend, J. Freundlich, G. Lamichhane. “Non-classical transpeptidases yield insight into new antibacterials.” Nat. Chem. Biol., 2017, 13, 54-61. 6. R. Mattoo, E.P. Lloyd, A. Kaushik, P. Kumar, J.L. Brunelle, C.A. Townsend, G. Lamichhane. “A molecular vulnerability in Mycobacterium avium: L,D- transpeptidase orthologue in Mycobacterium avium is constitutively expressed and inhibited by carbapenems.” Future Microbiol., 2017 in press. Submitted or In Preparation: 7. Y.H. Pan, L.A. Basta, H.G. Saaverdra, E.P. Lloyd, P. Kumar, R. Mattoo, C.A. Townsend, M.A. Bianchet, G. Lamichhane. “Structural insight into the mechanism of inhibition of Mycobacterium tuberculosis L,D-transpeptidase 2 by Biapenem and Tebipenem.” Manuscript submitted for review.
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