Using Diphenylphosphoryl Azide (DPPA) for the facile synthesis of biodegradable antiseptic random copolypeptides

Abstract

We have developed a facile method for the large-scale synthesis of random copolypeptides composed of multiple (i.e. cationic, hydrophobic, and hydrophilic) amino acids and have optimized their relative ratios for broad-spectrum antibacterial effect. The copolypeptides obtained have measured compositions close to the design ratios in spite of the differing reactivities of the different amino acids. An optimised random copolypeptide of lysine, leucine and serine (denoted as KLS-3) mimicking the composition of LL-37 host defense peptide gives broad spectrum antibacterial activity against clinically relevant Gram-negative and Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PAO1) with minimum inhibitory concentrations (MICs) of 32-64 μg/mL, as well as good MICs against multi-drug resistant Gram-negative bacteria of E. coli EC 958 (64 μg/mL) and Klebsellia pneumonia PTR3 (128 μg/mL). This method can be applied to the facile large-scale copolymerization of multiple amino acids, including unnatural amino acids, to make effective antibacterial copolypeptides.