6TMC

VIM-2_1dh-Triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-beta-lactamases

6TMC の概要

• エントリーDOI: 10.2210/pdb6tmc/pdb
• 分子名称: Beta-lactamase class B VIM-2, 4-[2-(phenylsulfonyl)ethyl]-5-(propan-2-yloxymethyl)-1~{H}-1,2,3-triazole, ZINC ION, ... (6 entities in total)
• 機能のキーワード: metallo-beta-lactamase inhibitor, nh-triazole, inhibition properties, crystal structure., antibiotic
• 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: 28936.95

構造登録者

Leiros, H.-K.S.,Christopeit, T. (登録日: 2019-12-04, 公開日: 2020-07-22, 最終更新日: 2024-01-24)

主引用文献

Muhammad, Z.,Skagseth, S.,Boomgaren, M.,Akhter, S.,Frohlich, C.,Ismael, A.,Christopeit, T.,Bayer, A.,Leiros, H.S.
Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-beta-lactamases.
Bioorg.Med.Chem., 28:115598-115598, 2020

PubMed Abstract: Metallo-β-lactamases (MBLs) are an emerging cause of bacterial antibiotic resistance by hydrolysing all classes of β-lactams except monobactams, and the MBLs are not inhibited by clinically available serine-β-lactamase inhibitors. Two of the most commonly encountered MBLs in clinical isolates worldwide - the New Delhi metallo-β-lactamase (NDM-1) and the Verona integron-encoded metallo-β-lactamase (VIM-2) - are included in this study. A series of several NH-1,2,3-triazoles was prepared by a three-step protocol utilizing Banert cascade reaction as the key step. The inhibitor properties were evaluated in biochemical assays against the MBLs VIM-2, NDM-1 and GIM-1, and VIM-2 showed IC values down to nanomolar range. High-resolution crystal structures of four inhibitors in complex with VIM-2 revealed hydrogen bonds from the triazole inhibitors to Arg228 and to the backbone of Ala231 or Asn233, along with hydrophobic interactions to Trp87, Phe61 and Tyr67. The inhibitors show reduced MIC in synergy assays with Pseudomonas aeruginosa and Escherichia coli strains harbouring VIM enzymes. The obtained results will be useful for further structural guided design of MBL inhibitors.

PubMed: 32631568
DOI: 10.1016/j.bmc.2020.115598

実験手法

X-RAY DIFFRACTION (1.4 Å)