Skepper, CK;
Armstrong, D;
Balibar, CJ;
Bauer, D;
Bellamacina, C;
Benton, BM;
Bussiere, D;
De Pascale, G;
De Vicente, J;
Dean, CR;
et al.
Skepper, CK; Armstrong, D; Balibar, CJ; Bauer, D; Bellamacina, C; Benton, BM; Bussiere, D; De Pascale, G; De Vicente, J; Dean, CR; Dhumale, B; Fisher, LM; Fuller, J; Fulsunder, M; Holder, LM; Hu, C; Kantariya, B; Lapointe, G; Leeds, JA; Li, X; Lu, P; Lvov, A; Ma, S; Madhavan, S; Malekar, S; McKenney, D; Mergo, W; Metzger, L; Moser, HE; Mutnick, D; Noeske, J; Osborne, C; Patel, A; Patel, D; Patel, T; Prajapati, K; Prosen, KR; Reck, F; Richie, DL; Rico, A; Sanderson, MR; Satasia, S; Sawyer, WS; Selvarajah, J; Shah, N; Shanghavi, K; Shu, W; Thompson, KV; Traebert, M; Vala, A; Vala, L; Veselkov, DA; Vo, J; Wang, M; Widya, M; Williams, SL; Xu, Y; Yue, Q; Zang, R; Zhou, B; Rivkin, A
(2020)
Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.
J Med Chem, 63 (14).
pp. 7773-7816.
ISSN 1520-4804
https://doi.org/10.1021/acs.jmedchem.0c00347
SGUL Authors: Fisher, Larry Mark
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Abstract
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.
Item Type: | Article | ||||||||
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Additional Information: | This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.0c00347 | ||||||||
Keywords: | 0304 Medicinal and Biomolecular Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, 0305 Organic Chemistry, Medicinal & Biomolecular Chemistry | ||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | ||||||||
Journal or Publication Title: | J Med Chem | ||||||||
ISSN: | 1520-4804 | ||||||||
Language: | eng | ||||||||
Dates: |
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Publisher License: | Publisher's own licence | ||||||||
PubMed ID: | 32634310 | ||||||||
Go to PubMed abstract | |||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/112146 | ||||||||
Publisher's version: | https://doi.org/10.1021/acs.jmedchem.0c00347 |
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