PDBsum entry 6tmc

Antibiotic

PDB id: 6tmc

Contents

Protein chain

230 a.a.

Ligands

NL5

_OH

IOD

Metals

_ZN ×2

Waters ×278

PDB id:

6tmc

Name:

Antibiotic

Title:

Vim-2_1dh-triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-beta-lactamases

Structure:

Beta-lactamase class b vim-2. Chain: a. Synonym: blavim-2,class b carbapenemase vim-2,metallo beta-lactamase, metallo-beta lactamase protein,metallo-beta-lactamase vim-2,vim-2, vim-2 beta-lactamase,vim-2 class b metallo b-lactamase,vim-2 type metallo-beta-lactamase. Engineered: yes

Source:

Pseudomonas aeruginosa. Organism_taxid: 287. Gene: blavim-2, bla vim-2, bla-vim-2, blasvim-2, blavim2, blm, vim- 2, vim-2, paerug_p32_london_17_vim_2_10_11_06255. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.40Å R-factor: 0.158 R-free: 0.168

Authors:

H.-K.S.Leiros,T.Christopeit

Key ref:

Z.Muhammad et al. (2020). Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-β-lactamases. Bioorg Med Chem, 28, 115598. PubMed id: 32631568 DOI: 10.1016/j.bmc.2020.115598

Date:

04-Dec-19 Release date: 22-Jul-20

Protein chain

Q9K2N0  (Q9K2N0_PSEAI) -  Beta-lactamase from Pseudomonas aeruginosa

Seq: 266 a.a.

Struc: 231 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.bmc.2020.115598

Bioorg Med Chem 28:115598 (2020)

PubMed id: 32631568

Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-β-lactamases.

Z.Muhammad, S.Skagseth, M.Boomgaren, S.Akhter, C.Fröhlich, A.Ismael, T.Christopeit, A.Bayer, H.S.Leiros.

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 IC₅₀ 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.