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
| Autor: | Dominik Ausbacher, Johanna U. Ericson Sollid, Terkel Hansen, Marianne Hagensen Paulsen, Annette Bayer, Tor Haug, Magnus Engqvist, Morten B. Strøm, Trude Anderssen, Jeanette Hammer Andersen |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Gram-negative bacteria
VDP::Mathematics and natural scienses: 400::Chemistry: 440::Pharmaceutical chemistry: 448 Halogenation Stereochemistry Gram-positive bacteria Antimicrobial peptides Microbial Sensitivity Tests Gram-Positive Bacteria 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Mice Anti-Infective Agents Amide Drug Resistance Multiple Bacterial Beta-amino acids Drug Discovery Gram-Negative Bacteria Animals Humans 030304 developmental biology Pharmacology 0303 health sciences Synthetic mimics of antimicrobial peptides biology 010405 organic chemistry Multi-resistant bacteria Organic Chemistry SMAMPs General Medicine biology.organism_classification Antimicrobial Amides 0104 chemical sciences Multiple drug resistance Antibacterial chemistry ESBL Lipophilicity VDP::Matematikk og naturvitenskap: 400::Kjemi: 440::Legemiddelkjemi: 448 CARBA Peptidomimetics Bacteria |
| Popis: | Source at https://doi.org/10.1016/j.ejmech.2019.111671. 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. |
| Databáze: | OpenAIRE |
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