5T66

Crystal Structure of CTX-M-15 with 1C

5T66 の概要

• エントリーDOI: 10.2210/pdb5t66/pdb
• 関連するPDBエントリー: 5FQ9 5FQB 5FQC 5J8X
• 分子名称: Beta-lactamase, (3R)-3-(cyclohexylcarbonylamino)-2-oxidanyl-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid (3 entities in total)
• 機能のキーワード: serine-beta-lactamase, hydrolase, boronate inhibitor
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62989.37

構造登録者

Cahill, S.T.,Brem, J.,McDonough, M.A.,Schofield, C.J. (登録日: 2016-09-01, 公開日: 2017-02-15, 最終更新日: 2024-01-17)

主引用文献

Cahill, S.T.,Cain, R.,Wang, D.Y.,Lohans, C.T.,Wareham, D.W.,Oswin, H.P.,Mohammed, J.,Spencer, J.,Fishwick, C.W.,McDonough, M.A.,Schofield, C.J.,Brem, J.
Cyclic Boronates Inhibit All Classes of beta-Lactamases.
Antimicrob. Agents Chemother., 61:-, 2017

PubMed Abstract: β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyze their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Coproduction of MBLs and SBLs in resistant infections is thus of major clinical concern. The development of "dual-action" inhibitors, targeting both SBLs and MBLs, is of interest, but this is considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactamases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase CTX-M-15, the class C enzyme AmpC from , and class D OXA enzymes with carbapenem-hydrolyzing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small-molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis.

PubMed: 28115348
DOI: 10.1128/AAC.02260-16

実験手法

X-RAY DIFFRACTION (1.951 Å)