RIBOSOME TARGETING ANTIBIOTICS AS SCAFFOLDS FOR NOVEL BACTERIAL MEMBRANE DISRUPTORS

Infections caused by drug resistant and slow-growing bacteria are increasingly becoming a one of the greatest challenges of worldwide health organizations. The decrease in the efficacy of a large percentage of the current repertoire of clinically used antibiotics against these types of infections emphasizes the need for the development of novel antimicrobial agents that will effectively eradicate a broad spectrum of bacteria regardless of the bacterial cell cycle stage. 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 its intracellular resistance mechanisms, and therefore offer a solution to persistent infections.

In this study we used the ribosome targeting aminoglycoside antibiotic tobramycin, as a scaffold for the synthesis of novel bacterial membrane disruptors. We designed antimicrobial cationic amphiphiles by varying several structural parameters: the length of the hydrophobic residues attached to the aminoglycoside, the type and number of hydrophobic residues, the hydrophobicity/hydrophilicity ratio and the linkage between the hydrophobic and hydrophilic parts.^1-4

Antimicrobial activity, membrane selectivity and structure activity relationship were studied. Some of the cationic amphiphiles in this study demonstrated marked antimicrobial activity against a broad selection of Gram-positive and Gram-negative pathogens. These compounds, which no longer target the ribosome, were 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.

The results of this study demonstrate that it is possible to design aminoglycoside-base membrane targeting antibiotics which demonstrate enhanced selectivity to bacterial membranes.

^[1] Angew. Chem. Int. Ed., 2012, 51, 5652-5656.

^[2] Med. Chem. Commun. 2013, 4, 120-124.

^[3] Org. Lett., 2013, 15, 6144-6147.

^[4] Chem. Euro. J., 2015, 21, 4340-4349.