Tobramycin and Nebramine as Pseudo-Oligosaccharide Scaffolds for Development of Antimicrobial Cationic Amphiphiles.

Raphael Benhamou, Organic Chemistry, Tel Aviv University, Tel Aviv, Israel
Kfir Steinbuch, Organic Chemistry, Tel Aviv University, Tel Aviv, Israel

Antimicrobial cationic amphiphiles derived from aminoglycoside pseudo-oligosaccharide antibiotics interfere with the structure and function of bacterial membranes and offer a promising direction for the development of novel antibiotics. In this study we designed and synthesized cationic amphiphiles derived from the pseudo-trisaccharide aminoglycoside tobramycin and its pseudo-disaccharide segment nebramine. Antimicrobial activity, membrane selectivity, mode of action, and structure activity relationship aspects were studied. In designing the cationic amphiphiles we focused on varying the following parameters: the numbers of hydrophobic residues, the types of hydrophobic residues, and the hydrophobicity/hydrophilicity ratio. Some of the cationic amphiphiles in this study demonstrated marked antimicrobial activity, and one amphiphilic nebramine derivative proved effective against a broad selection of Gram positive and Gram negative pathogens; this compound was well over an order of magnitude more potent against the tested pathogens than the parent antibiotic tobramycin and the membrane-targeting antimicrobial peptide mixture gramicidin D that are in clinical use.