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

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 <b>4e</b> with 3,5-di-brominated benzylic side-chains. Derivative <b>4e</b> 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 <b>4e</b> 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 <b>4e</b> make them attractive as lead compounds for development of novel antimicrobial drugs.