作者
Colin K. Skepper,Duncan Armstrong,Carl J. Balibar,Daniel Bauer,Cornelia Bellamacina,Bret M. Benton,Dirksen E. 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,Xin Li,Peichao Lu,Anatoli Lvov,Sylvia Ma,Shravanthi Madhavan,Swapnil A. Malekar,David McKenney,Wosenu Mergo,Louis E. Metzger,Heinz Moser,Daniel Mutnick,J. Noeske,Colin Osborne,Avnish Patel,Darshit Patel,Tushar M. Patel,Krunal Prajapati,Katherine R. Prosen,Folkert Reck,Daryl L. Richie,Alice Rico,Mark Sanderson,Shailesh P. Satasia,William S. Sawyer,Jogitha Selvarajah,Nirav R. Shah,Kartik Shanghavi,Wei Shu,Katherine Thompson,Martin Traebert,Anand Vala,Lakhan Vala,D. A. Veselkov,Julie Vo,Michael Wang,Marcella Widya,S. Williams,Yan Xu,Yue Qin,Richard Zang,Bo Zhou,Alexey Rivkin
摘要
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.