To date, the concept of disrupting bacterial membranes as a strategy to develop antibiotics has been poorly exploited even though such antibiotics should be un-affected by the bacterial cell cycle, and therefore offer a solution to persistent infections. In addition, antimicrobial agents that act in the extracellular bacterial environment evade intracellular resistance mechanisms, and are therefore expected to maintain prolonged clinical efficacy. Finally, the development of membrane targeting antibiotics does not require cell permeability considerations which are often a significant challenge for drug designers. However, since membranes are common to all cells, avoiding potential cytotoxicity to eukaryotic cells through non-selective membrane disruption by bacterial membrane targeting antibiotics is a major challenge.
To explore the possibility of developing bacterial membrane targeting antibiotics with low levels of toxicity to eukaryotic cells, we chemically modified the aminoglycoside (AG) tobramycin, and prepared a selection of antimicrobial cationic amphiphiles. Several linear aliphatic chain tobramycin analogues differing in the chemical bond linking their hydrophobic and hydrophilic parts were synthesized and demonstrated high potency against a broad spectrum of bacteria with high levels of resistance to the parent antibiotic. These compounds target bacterial membranes and no longer target the ribosome as the parent antibiotic. Red blood cell hemolysis tests indicated that there is no correlation between the antimicrobial potency and the hemolytic activity of these antibacterials, and that the aliphatic chain length and the chemical linkage between the hydrophilic and hydrophobic parts of these molecules significantly affected the specificity towards bacterial membranes.
The results of this study demonstrate that it is possible to design AG-base membrane targeting antibiotics which demonstrate selectivity to bacterial membranes, and that further improvement in the selectivity level of these compounds through chemical modifications is possible and may lead to the discovery of novel antibiotics with a unique mode of action.
