A new strategy for total solid-phase synthesis of polymyxins

Abstract

Polymyxin B and E are used as a ‘last line’ therapy for infections caused by serious Gram-negative bacteria due to their highly efficient antibacterial activity and nephrotoxicity. Many research groups have been performed on designing polymyxin analogues by chemical synthesis in order to decrease the nephrotoxicity and increase the antibacterial activity simultaneously. In this study, we developed a new strategy for total solid phase synthesis of polymyxins and their analogues. This method is achieved by anchoring the amine side chain of Dab9 on resin first and on-resin cyclization at last. Comparing to the mostly used chemical synthetic method for polymyxins which involves solid phase peptide synthesis followed by liquid phase cyclization, the method reported here is more convenient and efficient. Therefore, this new strategy may be a good replacement for current chemical synthetic method in designing polymyxin analogues.