Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-β-lactamases. Issue 15 (1st August 2020)

• Record Type: Journal Article
• Authors: Muhammad, Zeeshan; Skagseth, Susann; Boomgaren, Marc; Akhter, Sundus; Fröhlich, Christopher; Ismael, Aya; Christopeit, Tony; Bayer, Annette; Leiros, Hanna-Kirsti S.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 15(2020)
• Publication Date: 2020-08-01
• Subjects: DMSO dimethyl sufoxide -- GIM German imipenemase -- IC50 half maximal inhibitory concentration -- IPM imipenem -- MBL metallo-β-lactamase -- NCF nitrocefin -- NDM New Delhi metallo-β-lactamase -- VIM-2 Verona integron-encoded metallo-β-lactamase; Metallo-β-lactamase inhibitor -- NH-triazole -- Inhibition properties -- Crystal structure -- Structural guided design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115598
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 N H-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.