7FVS

Crystal Structure of S. aureus gyrase in complex with 4-[[1-[(1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl)methyl]azetidin-3-yl]methylamino]-6-fluorochromen-2-one

7FVS の概要

• エントリーDOI: 10.2210/pdb7fvs/pdb
• Group deposition: A set of S. aureus gyrase BA fusion crystal structures (G_1002266)
• 分子名称: DNA gyrase subunit B,DNA gyrase subunit A Chimera, DNA (5'-D(*AP*GP*CP*CP*GP*TP*AP*GP*GP*GP*CP*CP*CP*TP*AP*CP*GP*GP*CP*T)-3'), MANGANESE (II) ION, ... (7 entities in total)
• 機能のキーワード: dna gyrase, topoisomerase;, isomerase
• 由来する生物種: Staphylococcus aureus subsp. aureus N315; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 169163.09

構造登録者

Xu, B.,Benz, J.,Cumming, J.G.,Kreis, L.,Rudolph, M.G. (登録日: 2023-04-18, 公開日: 2023-06-28, 最終更新日: 2023-08-16)

主引用文献

Cumming, J.G.,Kreis, L.,Kuhne, H.,Wermuth, R.,Vercruysse, M.,Kramer, C.,Rudolph, M.G.,Xu, Z.
Discovery of a Series of Indane-Containing NBTIs with Activity against Multidrug-Resistant Gram-Negative Pathogens.
Acs Med.Chem.Lett., 14:993-998, 2023

PubMed Abstract: The rise of multidrug-resistant (MDR) Gram-negative bacteria is a major global health problem necessitating the discovery of new classes of antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) target the clinically validated bacterial type II topoisomerases with a distinct binding site and mechanism of action to fluoroquinolone antibiotics, thus avoiding cross-resistance to this drug class. Here we report the discovery of a series of NBTIs incorporating a novel indane DNA binding moiety. X-ray cocrystal structures of compounds and bound to DNA gyrase-DNA were determined, revealing specific interactions with the enzyme binding pocket at the GyrA dimer interface and a long-range electrostatic interaction between the basic amine in the linker and the carboxylate of Asp83. Exploration of the structure-activity relationship within the series led to the identification of lead compound , which showed potent broad-spectrum activity against a panel of MDR Gram-negative bacteria.

PubMed: 37465290
DOI: 10.1021/acsmedchemlett.3c00187

実験手法

X-RAY DIFFRACTION (2.16 Å)