Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors

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Article

Prandina, Anthony^1,2  Radix, Sylvie²  Le Borgne, Marc²  Jordheim, Lars Petter³  Bousfiha, Zineb³  Frohlich, Christopher^4,5  Leiros, Hanna-Kirsti S.⁵  Samuelsen, Orjan^4,6  Frovold, Espen¹  Rongved, Pal¹  Astrand, Ove Alexander Hogmoen¹ 

[1] Univ Oslo, Sch Pharm, Dept Pharmaceut Chem, POB 1068 Blindern, N-0316 Oslo, Norway

[2] Univ Lyon 1, Univ Lyon, SFR Sante Lyon Est CNRS UMS3453 INSERM US7, Fac Pharm ISPB,EA 4446 Bioact Mol & Med Chem, F-69373 Lyon 08, France

[3] Univ Claude Bernard Lyon 1, Univ Lyon, CNRS,UMR5286, Ctr Leon Berard,Ctr Rech Cancerol Lyon,INSERM 105, 8 Ave Rockefeller, F-69373 Lyon 8, France

[4] Univ Hosp North Norway, Norwegian Natl Advisory Unit Detect Antimicrobial, Dept Microbiol & Infect Control, N-9038 Tromso, Norway

[5] UiT Arctic Univ Norway, Norwegian Struct Biol Ctr NorStruct, Dept Chem, N-9037 Tromso, Norway

[6] UiT Arctic Univ Norway, Dept Pharm, N-9037 Tromso, Norway

关键词: MBL-producing gram negative bacteria;    Multidrug resistant bacteria;    Zinc chelators;    Dipicolylamine derivatives;    Antibiotic adjuvant;   

DOI  :  10.1016/j.tet.2019.02.004

来源: Elsevier

【 摘 要 】

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-beta-lactamases (MBLs). The nature of the linker was modified in a structure-activity relationship study. Compound 1i, 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 of 1i against VIM-2 was 9.8 and 2.2 mu M after 5 and 20 min, respectively. Compound 1i also showed intrinsic toxicity against three eukaryotic human tumoral cell lines between 50 and 120 mu M. (C) 2019 Elsevier Ltd. All rights reserved.

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