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

• Published in: Bioorganic & medicinal chemistry Vol. 28; no. 15; p. 115598
• Main Authors: Muhammad, Zeeshan, Skagseth, Susann, Boomgaren, Marc, Akhter, Sundus, Fröhlich, Christopher, Ismael, Aya, Christopeit, Tony, Bayer, Annette, Leiros, Hanna-Kirsti S.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2020; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Chemistry: 440; Crystal structure; Inhibition properties; Kjemi: 440; Life Sciences & Biomedicine; Matematikk og Naturvitenskap: 400; Mathematics and natural science: 400; Metallo-β-lactamase inhibitor; NH-triazole; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structural guided design; VDP; VIM-2; DMSO; IPM; Metallo-β-lactamase inhibitor; GIM; Inhibition properties; NCF; Structural guided design; MBL; NDM; IC50; NH-triazole; Crystal structure; BIOCHEMICAL-CHARACTERIZATION; CRYSTAL-STRUCTURES; Metallo-beta-lactamase inhibitor; DISCOVERY; UNSATURATED AZIDES; NDM-1; PSEUDOMONAS-AERUGINOSA; BANERT CASCADE; RADIATION-DAMAGE; SCAFFOLDS
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2020.115598

[Display omitted] 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.