Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

Autor:	Skepper CK; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Armstrong D; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Balibar CJ; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Bauer D; Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland., Bellamacina C; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Benton BM; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Bussiere D; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., De Pascale G; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., De Vicente J; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Dean CR; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Dhumale B; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Fisher LM; Molecular and Clinical Sciences Research Institute, St George's University of London, London SW17 0RE, U.K., Fuller J; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Fulsunder M; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Holder LM; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Hu C; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Kantariya B; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Lapointe G; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Leeds JA; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Li X; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Lu P; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Lvov A; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Ma S; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Madhavan S; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Malekar S; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., McKenney D; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Mergo W; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Metzger L; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Moser HE; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Mutnick D; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Noeske J; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Osborne C; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Patel A; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Patel D; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Patel T; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Prajapati K; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Prosen KR; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Reck F; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Richie DL; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Rico A; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Sanderson MR; Randall Centre for Cell and Molecular Biophysics, King's College, Guy's Campus, London Bridge, London SE1 1UL, U.K., Satasia S; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Sawyer WS; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Selvarajah J; Molecular and Clinical Sciences Research Institute, St George's University of London, London SW17 0RE, U.K., Shah N; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Shanghavi K; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Shu W; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Thompson KV; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Traebert M; Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland., Vala A; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Vala L; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India., Veselkov DA; Randall Centre for Cell and Molecular Biophysics, King's College, Guy's Campus, London Bridge, London SE1 1UL, U.K., Vo J; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Wang M; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Widya M; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Williams SL; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Xu Y; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Yue Q; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Zang R; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Zhou B; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States., Rivkin A; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Jul 23; Vol. 63 (14), pp. 7773-7816. Date of Electronic Publication: 2020 Jul 07.
DOI:	10.1021/acs.jmedchem.0c00347
Abstrakt:	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(1 H )-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.
Databáze:	MEDLINE
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