Journal of medicinal chemistry · 2020

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

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

Аннотация

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.

Предметные рубрики MeSH

Anti-Bacterial Agents Binding Sites Cell Line, Tumor DNA Gyrase DNA Topoisomerase IV Drug Resistance, Bacterial Fluoroquinolones Gram-Negative Bacteria Humans Microbial Sensitivity Tests Molecular Structure Structure-Activity Relationship Topoisomerase II Inhibitors

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

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Аннотация

Предметные рубрики MeSH