The growing emergence of pathogenic bacteria with clinical significant resistance to conventional antibiotics is a major public health concern. There has been a revival of polymyxins which have serious issues of nephrotoxicity/ neurotoxicity as antibiotics of last resort. Resistance to polymyxins means that no antibiotics are available for the treatment of serious Gram-negative infections cause by polymyxin-resistant “superbugs”. It is difficult for bacteria to develop resistance to antimicrobial peptides that do not have specific targets as their mode of action generally involves non-specific interactions with the cytoplasmic membrane whereby peptide accumulation causes increased permeability and hence, cell death.
We have designed 26-residue all D-conformation amphipathic alpha-helical antimicrobial peptides (AMPs) whose sole target is the cytoplasmic membrane of bacteria (no stereochemical target). These peptides are resistant to proteolytic enzyme degradation, enhancing their use as therapeutic agents. Native AMPs lack specificity between prokaryotic and eukaryotic cells and are too toxic to be used for systemic treatment of bacterial infections. Our discovery of “specificity determinants” and the incorporation of unusual amino acids (Dab and Dap) on the polar face resulted in the complete removal of toxicity as measured by lysis of human red blood cells under the most stringent conditions.