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Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

Skepper, Colin and Armstrong, Duncan and Balibar, Carl and Bauer, Daniel and Bellamacina, Cornelia and Benton, Bret and Bussiere, Dirksen and Holder, Lauren and Dangi, Veer and De Pascale, Gianfranco and De Vicente Fidalgo, Javier and Dean, Charles and Dhumale, Bhavesh and Mark, Fisher and Fuller, John and Fulsunder, Mangesh and Hu, Cheng and Kantariya, Bhavin and Lapointe, Guillaume and Leeds, Jennifer and Li, Xiaolin and Lu, Peichao and Lvov, Anatoli and Ma, Sylvia and Madhavan, Shravanthi and Malekar, Swapnil and Mckenney, David and Mergo, Wosenu and Metzger Iv, Louis and Moser, Heinz and Mutnick, Daniel and Noeske, Jonas and Osborne, Colin and Pal, Arani and Patel, Ashish and Patel, Darshit and Patel, Tushar and Prajapati, Krunal and Prosen, Katie and Reck, Folkert and Richie, Daryl and Rico, Alice and Sanderson, Mark and Satasia, Shailesh and Sawyer, William and Selvarajah, Jogitha and Shafer, Cynthia and Shah, Nirav and Shangavi, Kartik and Shu, Wei and Thompson, Katherine and Vala, Anand and Veselkov, Dennis and Vo, Jason and Wang, Michael and Widya, Marcella and Williams, Sarah and Xu, Yongjin and Yue, Qin and Zhang, Richard and 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

Abstract

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
URI: https://oak.novartis.com/id/eprint/41863

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