Chemical Conversion of Natural Polymyxin B and Colistin to Their <i>N</i>-Terminal Derivatives

Abstract

Abstract The chemical conversions of natural polymyxin B and colistin, which are fatty-acylated cyclic decapeptides, to polymyxin (2–10) and colistin (2–10) derivatives were examined. The Nα-free and side chain Nγ-protected nonapeptides, i.e., tetrakis(Nγ-trifluoroacetyl)–polymyxin B (2–10) and tetrakis(Nγ-trifluoroacetyl)–colistin (2–10), were prepared by trifluoroacetylation of polymyxin B and colistin, followed by chemical cleavage with 50% methanesulfonic acid to remove Nα-alkanoyl–Nγ-trifluoroacetyl–Dab–OH. The Nγ-protected nonapeptides were useful starting materials for the semi-synthesis of N-terminal derivatives by selective Nα-acylation at Thr2, followed by the removal of the Nγ-trifluoroacetyl protecting group with aqueous piperidine. Further, myristoyl–polymyxin B (2–10) and myristoyl–colistin (2–10) retained their antimicrobial activity with an MIC of 2–4 nmol mL−1 against Escherichia coli, Salmonella Typhimurium, and Pseudomonas aeruginosa. They also retained their high lipopolysaccahride (LPS) binding activity. Acetyl–polymyxin B (2–10) and acetyl–colistin (2–10) exhibited very low biological activities, except for a high bactericidal activity specifically against Pseudomonas aeruginosa with an MIC of 2 nmol mL−1. The distinct sensitivity of three Gram-negative bacteria tested toward acetyl-nonapeptides suggested that the N-terminal hydrophobic character of the fatty-acylated polymyxin peptides was necessary for the bactericidal activity against Escherichia coli and Salmonella Typhimurium, but not against Pseudomonas aeruginosa.