6VHS

Crystal structure of CTX-M-14 in complex with beta-lactamase inhibitor ETX1317

6VHS の概要

• エントリーDOI: 10.2210/pdb6vhs/pdb
• 分子名称: Beta-lactamase, (2R)-({[(3R,6S)-6-carbamoyl-1-formyl-4-methyl-1,2,3,6-tetrahydropyridin-3-yl]amino}oxy)(fluoro)acetic acid, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: ctx-m-14, beta-lactamase, b-lactamase, etx3517, etx-3517, avibactam, dbo, hydrolase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 56992.36

構造登録者

Sacco, M.D.,Chen, Y. (登録日: 2020-01-10, 公開日: 2020-08-26, 最終更新日: 2024-10-23)

主引用文献

Durand-Reville, T.F.,Comita-Prevoir, J.,Zhang, J.,Wu, X.,May-Dracka, T.L.,Romero, J.A.C.,Wu, F.,Chen, A.,Shapiro, A.B.,Carter, N.M.,McLeod, S.M.,Giacobbe, R.A.,Verheijen, J.C.,Lahiri, S.D.,Sacco, M.D.,Chen, Y.,O'Donnell, J.P.,Miller, A.A.,Mueller, J.P.,Tommasi, R.A.
Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine beta-Lactamases.
J.Med.Chem., 63:12511-12525, 2020

PubMed Abstract: Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward β-lactam antibiotics. The hydrolytic enzymes called β-lactamases are responsible for a large proportion of the resistance phenotype. β-Lactamase inhibitors (BLIs) can be administered in combination with β-lactam antibiotics to negate the action of the β-lactamases, thereby restoring activity of the β-lactam. Newly developed BLIs offer some advantage over older BLIs in terms of enzymatic spectrum but are limited to the intravenous route of administration. Reported here is a novel, orally bioavailable diazabicyclooctane (DBO) β-lactamase inhibitor. This new DBO, ETX1317, contains an endocyclic carbon-carbon double bond and a fluoroacetate activating group and exhibits broad spectrum activity against class A, C, and D serine β-lactamases. The ester prodrug of ETX1317, ETX0282, is orally bioavailable and, in combination with cefpodoxime proxetil, is currently in development as an oral therapy for multidrug resistant and carbapenem-resistant infections.

PubMed: 32658473
DOI: 10.1021/acs.jmedchem.0c00579

実験手法

X-RAY DIFFRACTION (1.28 Å)