Kildahl-Andersen Geir, Schnaars Christian, Prandina Anthony, Radix Sylvie, Le Borgne Marc, Jordheim Lars Petter, Gjøen Tor, Andresen Adriana Magalhães Santos, Lauksund Silje, Fröhlich Christopher, Samuelsen Ørjan, Rongved Pål, Åstrand Ove Alexander Høgmoen
Department of Pharmaceutical Chemistry , School of Pharmacy , University of Oslo , PO Box 1068 Blindern , 0316 Oslo , Norway . Email:
EA 4446 Bioactive Molecules and Medicinal Chemistry , Faculté de Pharmacie - ISPB , Université de Lyon , Université Lyon 1 , SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7 , F-69373 , Lyon cedex 08 , France.
Medchemcomm. 2019 Mar 8;10(4):528-537. doi: 10.1039/c8md00578h. eCollection 2019 Apr 1.
The syntheses of metallo-β-lactamase inhibitors comprising chelating moieties, with varying zinc affinities, and peptides partly inspired from bacterial peptide sequences, have been undertaken. The zinc chelator strength was varied using the following chelators, arranged in order of ascending binding affinity: dipicolylamine (DPA, tridentate), dipicolyl-1,2,3-triazolylmethylamine (DPTA, tetradentate) dipicolyl ethylenediamine (DPED, tetradentate) and trispicolyl ethylenediamine (TPED, pentadentate). The chosen peptides were mainly based on the known sequence of the C-terminus of the bacterial peptidoglycan precursors. Biological evaluation on clinical bacterial isolates, harbouring either the NDM-1 or VIM-2 metallo-β-lactamase, showed a clear relationship between the zinc chelator strength and restoration of meropenem activity. However, evaluation of toxicity on different cancer cell lines demonstrated a similar trend, and thus inclusion of the bacterial peptides did possess rather high toxicity towards eukaryotic cells.
已开展了金属β-内酰胺酶抑制剂的合成工作，这些抑制剂包含具有不同锌亲和力的螯合部分以及部分受细菌肽序列启发的肽段。使用以下螯合剂改变锌螯合剂的强度，按结合亲和力升序排列：二吡啶甲胺（DPA，三齿）、二吡啶基-1,2,3-三唑基甲胺（DPTA，四齿）、二吡啶基乙二胺（DPED，四齿）和三吡啶基乙二胺（TPED，五齿）。所选肽段主要基于细菌肽聚糖前体C端的已知序列。对携带NDM-1或VIM-2金属β-内酰胺酶的临床细菌分离株进行的生物学评估表明，锌螯合剂强度与美罗培南活性的恢复之间存在明显关系。然而，对不同癌细胞系的毒性评估显示出类似趋势，因此包含细菌肽段对真核细胞确实具有相当高的毒性。
