6SP6

Ultra-high Resolution Crystal Structure of the CTX-M-15 Extended-Spectrum beta-Lactamase in Complex with Taniborbactam (VNRX-5133)

6SP6 の概要

• エントリーDOI: 10.2210/pdb6sp6/pdb
• 分子名称: Beta-lactamase, SULFATE ION, (3~{R})-3-[2-[4-(2-azanylethylamino)cyclohexyl]ethanoylamino]-2-oxidanyl-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid, ... (6 entities in total)
• 機能のキーワード: beta-lactamase, hydrolase, antibiotic resistance, beta-lactam hydrolysis
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29154.57

構造登録者

Docquier, J.D.,Pozzi, C.,De Luca, F.,Benvenuti, M.,Mangani, S. (登録日: 2019-08-31, 公開日: 2020-01-22, 最終更新日: 2024-10-16)

主引用文献

Liu, B.,Trout, R.E.L.,Chu, G.H.,McGarry, D.,Jackson, R.W.,Hamrick, J.C.,Daigle, D.M.,Cusick, S.M.,Pozzi, C.,De Luca, F.,Benvenuti, M.,Mangani, S.,Docquier, J.D.,Weiss, W.J.,Pevear, D.C.,Xerri, L.,Burns, C.J.
Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-beta-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections.
J.Med.Chem., 63:2789-2801, 2020

PubMed Abstract: A major resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent β-lactamases can now confer resistance to other β-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of β-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-β-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum β-lactamase inhibitor. In vitro and in vivo studies demonstrated that restored the activity of β-lactam antibiotics against carbapenem-resistant and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.

PubMed: 31765155
DOI: 10.1021/acs.jmedchem.9b01518

実験手法

X-RAY DIFFRACTION (1.1 Å)