Journal of medicinal chemistry · 2021

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

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Lapointe Guillaume, Skepper Colin K, Holder Lauren M, Armstrong Duncan, Bellamacina Cornelia, Blais Johanne, Bussiere Dirksen, Bian Jianwei, Cepura Cody, Chan Helen, Dean Charles R, De Pascale Gianfranco, Dhumale Bhavesh, Fisher L Mark, Fulsunder Mangesh, Kantariya Bhavin, Kim Julie, King Sean, Kossy Lauren, Kulkarni Upendra, Lakshman Jay, Leeds Jennifer A, Ling Xiaolan, Lvov Anatoli, Ma Sylvia, Malekar Swapnil, McKenney David, Mergo Wosenu, Metzger Louis, Mhaske Keshav, Moser Heinz E, Mostafavi Mina, Namballa Sunil, Noeske Jonas, Osborne Colin, Patel Ashish, Patel Darshit, Patel Tushar, Piechon Philippe, Polyakov Valery, Prajapati Krunal, Prosen Katherine R, Reck Folkert, Richie Daryl L, Sanderson Mark R, Satasia Shailesh, Savani Bhautik, Selvarajah Jogitha, Sethuraman Vijay, Shu Wei, Tashiro Kyuto, Thompson Katherine V, Vaarla Krishniah, Vala Lakhan, Veselkov Dennis A, Vo Jason, Vora Bhavesh, Wagner Trixie, Wedel Laura, Williams Sarah L, Yendluri Satya, Yue Qin, Yifru Aregahegn, Zhang Yong, Rivkin Alexey

Аннотация

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.

Предметные рубрики MeSH

Animals Anti-Bacterial Agents DNA Gyrase DNA Topoisomerase IV Drug Design Drug Resistance, Bacterial Fluoroquinolones Mice Staphylococcus aureus Topoisomerase II Inhibitors

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH