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Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

Research output: Contribution to journalArticle

Colin K. Skepper, Duncan Armstrong, Carl J. Balibar, Daniel Bauer, Cornelia Bellamacina, Bret M. Benton, Dirksen Bussiere, Gianfranco De Pascale, Javier De Vicente, Charles R. Dean, Bhavesh Dhumale, L. Mark Fisher, John Fuller, Mangesh Fulsunder, Lauren M. Holder, Cheng Hu, Bhavin Kantariya, Guillaume Lapointe, Jennifer A. Leeds, Xiaolin Li & 35 more Peichao Lu, Anatoli Lvov, Sylvia Ma, Shravanthi Madhavan, Swapnil Malekar, David Mckenney, Wosenu Mergo, Louis Metzger, Heinz E. Moser, Daniel Mutnick, Jonas Noeske, Colin Osborne, Ashish Patel, Darshit Patel, Tushar Patel, Krunal Prajapati, Katherine R. Prosen, Folkert Reck, Daryl L. Richie, Alice Rico, Mark R. Sanderson, Shailesh Satasia, William S. Sawyer, Jogitha Selvarajah, Nirav Shah, Kartik Shanghavi, Wei Shu, Katherine V. Thompson, Dennis A. Veselkov, Sarah L. Williams, Yongjin Xu, Qin Yue, Richard Zang, Bo Zho, Alexey Rivkin

Original languageEnglish
Pages (from-to)7773-7816
Number of pages44
JournalJournal of Medicinal Chemistry
Issue number14
Early online date7 Jul 2020
Publication statusPublished - 23 Jul 2020

King's Authors


Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

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