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Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

Skepper, Colin, Armstrong, Duncan, Balibar, Carl, Bauer, Daniel, Bellamacina, Cornelia, Benton, Bret, Bussiere, Dirksen, Holder, Lauren, Dangi, Veer, De Pascale, Gianfranco, De Vicente Fidalgo, Javier, Dean, Charles, Dhumale, Bhavesh, Mark, Fisher, Fuller, John, Fulsunder, Mangesh, Hu, Cheng, Kantariya, Bhavin, Lapointe, Guillaume, Leeds, Jennifer, Li, Xiaolin, Lu, Peichao, Lvov, Anatoli, Ma, Sylvia, Madhavan, Shravanthi, Malekar, Swapnil, Mckenney, David, Mergo, Wosenu, Metzger Iv, Louis, Moser, Heinz, Mutnick, Daniel, Noeske, Jonas, Osborne, Colin, Pal, Arani, Patel, Ashish, Patel, Darshit, Patel, Tushar, Prajapati, Krunal, Prosen, Katie, Reck, Folkert, Richie, Daryl, Rico, Alice, Sanderson, Mark, Satasia, Shailesh, Sawyer, William, Selvarajah, Jogitha, Shafer, Cynthia, Shah, Nirav, Shangavi, Kartik, Shu, Wei, Thompson, Katherine, Vala, Anand, Veselkov, Dennis, Vo, Jason, Wang, Michael, Widya, Marcella, Williams, Sarah, Xu, Yongjin, Yue, Qin, Zhang, Richard, Zhou, Bo and Rivkin, Alexey (2020) Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria. Journal of Medicinal Chemistry, 63 (14). pp. 7773-7816. ISSN 0022-26231520-4804


Since their discovery over five 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.

Item Type: Article
Date Deposited: 17 Nov 2020 00:45
Last Modified: 17 Nov 2020 00:45


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