2. Academic Validation
  3. Antimicrobial activity of amphipathic α,α-disubstituted β-amino amide derivatives against ESBL - CARBA producing multi-resistant bacteria; effect of halogenation, lipophilicity and cationic character

Antimicrobial activity of amphipathic α,α-disubstituted β-amino amide derivatives against ESBL - CARBA producing multi-resistant bacteria; effect of halogenation, lipophilicity and cationic character

  • Eur J Med Chem. 2019 Dec 1:183:111671. doi: 10.1016/j.ejmech.2019.111671.
Marianne H Paulsen 1,  Dominik Ausbacher 2,  Annette Bayer 3,  Magnus Engqvist 4,  Terkel Hansen 1,  Tor Haug 5,  Trude Anderssen 1,  Jeanette H Andersen 6,  Johanna U Ericson Sollid 7,  Morten B Strøm 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, Faculty of Health Sciences, UiT - The Arctic University of Norway, NO-9037, Tromsø, Norway.
  • 2 Department of Pharmacy, Faculty of Health Sciences, UiT - The Arctic University of Norway, NO-9037, Tromsø, Norway; Hospital Pharmacy of North Norway Trust, NO-9038, Tromsø, Norway.
  • 3 Department of Chemistry, Faculty of Science and Technology, UiT - The Arctic University of Norway, NO-9037, Tromsø, Norway. Electronic address: annette.bayer@uit.no.
  • 4 Department of Chemistry, Faculty of Science and Technology, UiT - The Arctic University of Norway, NO-9037, Tromsø, Norway.
  • 5 The Norwegian College of Fishery Science, Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, NO-9037, Tromsø, Norway.
  • 6 Marbio, Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, NO-9037, Tromsø, Norway.
  • 7 Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, NO-9037, Tromsø, Norway.
  • 8 Department of Pharmacy, Faculty of Health Sciences, UiT - The Arctic University of Norway, NO-9037, Tromsø, Norway. Electronic address: morten.strom@uit.no.
PMID: 31536892 DOI: 10.1016/j.ejmech.2019.111671
Abstract

The rapid emergence and spread of multi-resistant bacteria have created an urgent need for new antimicrobial agents. We report here a series of amphipathic α,α-disubstituted β-amino amide derivatives with activity against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum β-lactamase - carbapenemase (ESBL-CARBA) production. A variety of halogenated aromatic side-chains were investigated to improve antimicrobial potency and minimize formation of Phase I metabolites. Net positive charge and cationic character of the derivatives had an important effect on toxicity against human cell lines. The most potent and selective derivative was the diguanidine derivative 4e with 3,5-di-brominated benzylic side-chains. Derivative 4e displayed minimum inhibitory concentrations (MIC) of 0.25-8 μg/mL against Gram-positive and Gram-negative reference strains, and 2-32 μg/mL against multi-resistant clinical isolates. Derivative 4e showed also low toxicity against human red blood cells (EC50 > 200 μg/mL), human hepatocyte carcinoma cells (HepG2: EC50 > 64 μg/mL), and human lung fibroblast cells (MRC-5: EC50 > 64 μg/mL). The broad-spectrum antimicrobial activity and low toxicity of diguanylated derivatives such as 4e make them attractive as lead compounds for development of novel antimicrobial drugs.

Keywords

Antibacterial; Antimicrobial peptides; Beta-amino acids; CARBA; ESBL; Multi-resistant bacteria; Peptidomimetics; SMAMPs; Synthetic mimics of antimicrobial peptides.

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