6ZGM

Crystal Structure of the VIM-2 Acquired Metallo-beta-Lactamase in Complex with the thiazolecarboxylate inhibitor ANT2681

6ZGM の概要

• エントリーDOI: 10.2210/pdb6zgm/pdb
• 分子名称: Metallo-beta-lactamase VIM-2-like protein, ZINC ION, ACETATE ION, ... (5 entities in total)
• 機能のキーワード: metallo-beta-lactamase, triazole-thione inhibitor, antibiotic resistance, carbapenem-hydrolyzing beta-lactamase, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26289.02

構造登録者

Docquier, J.D.,Pozzi, C.,Marcoccia, F.,De Luca, F.,Benvenuti, M.,Mangani, S. (登録日: 2020-06-19, 公開日: 2020-09-02, 最終更新日: 2024-01-24)

主引用文献

Davies, D.T.,Leiris, S.,Sprynski, N.,Castandet, J.,Lozano, C.,Bousquet, J.,Zalacain, M.,Vasa, S.,Dasari, P.K.,Pattipati, R.,Vempala, N.,Gujjewar, S.,Godi, S.,Jallala, R.,Sathyap, R.R.,Darshanoju, N.A.,Ravu, V.R.,Juventhala, R.R.,Pottabathini, N.,Sharma, S.,Pothukanuri, S.,Holden, K.,Warn, P.,Marcoccia, F.,Benvenuti, M.,Pozzi, C.,Mangani, S.,Docquier, J.D.,Lemonnier, M.,Everett, M.
ANT2681: SAR Studies Leading to the Identification of a Metallo-beta-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-ProducingEnterobacteriaceae.
Acs Infect Dis., 6:2419-2430, 2020

PubMed Abstract: The clinical effectiveness of the important β-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-β-lactamase (MBL) enzymes. To address this resistance issue, multiple β-lactam/β-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.

PubMed: 32786279
DOI: 10.1021/acsinfecdis.0c00207

実験手法

X-RAY DIFFRACTION (1.65 Å)