Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors. Issue 11 (15th March 2019)

• Record Type: Journal Article
• Authors: Prandina, Anthony; Radix, Sylvie; Le Borgne, Marc; Jordheim, Lars Petter; Bousfiha, Zineb; Fröhlich, Christopher; Leiros, Hanna-Kirsti S.; Samuelsen, Ørjan; Frøvold, Espen; Rongved, Pål; Åstrand, Ove Alexander Høgmoen
• Is Part Of: Tetrahedron. Volume 75:Issue 11(2019)
• Page Start: 1525
• Page End: 1540
• Publication Date: 2019-03-15
• Subjects: MBL-producing gram negative bacteria -- Multidrug resistant bacteria -- Zinc chelators -- Dipicolylamine derivatives -- Antibiotic adjuvant; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2019.02.004
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: Antibiotics are key drugs in modern healthcare, especially in hospitals, where multiresistant bacteria resides and is a potential threat to human health. In the present work, a new series of adjuvants working synergistically with the carbapenem meropenem, in which a selective zinc-chelating agent was covalently linked to the small bacterial peptide D -Ala- D -Ala, was synthesized and tested against VIM-2 and NDM-1 metallo-β-lactamases (MBLs). The nature of the linker was modified in a structure-activity relationship study. Compound1i, having an ethyl piperidine linker, lowered the MIC of meropenem from 32 to 64 mg/L to 2 and 1–2 mg/L against VIM-2- and NDM-1-producing clinical isolates, respectively. The IC50 value of1i against VIM-2 was 9.8 and 2.2 μM after 5 and 20 min, respectively. Compound1i also showed intrinsic toxicity against three eukaryotic human tumoral cell lines between 50 and 120 μM. Graphical abstract: Image 1