ABSTRACT
Twelve N-terminal analogs of des-fatty acyl-polymyxin B (Des-FA-[X(1)]-PMB, X=various amino acids or peptides) were synthesized and examined for their antimicrobial activity against Escherichia coli (E. coli), Salmonella Typhimurium (S. Typhimurium) and Pseudomonas aeruginosa (P. aeruginosa). It was found that Des-FA-[Dap(1)]-, Des-FA-[Ser(1)]-, Des-FA-[Dab-Dab-Dab(1)]- and Des-FA-[Arg-Arg-Arg(1)]-PMB had potent activity only against P. aeruginosa, with MIC values of 0.5-1 nmol/ml. Analogs in which X was Lys, Arg, Leu or Ala did not have increased antimicrobial activity against the three bacterial species tested compared with the lead compounds Des-FA-[Dab(1)]-PMB and polymyxin B (PMB). Des-FA-[Trp(1)]-PMB and Des-FA-[Phe(1)]-PMB had reduced activity against P. aeruginosa. The results indicate that compact hydrophilic amino acids (C3) or basic tripeptides at the N-terminal provide specificity for bactericidal activity towards P. aeruginosa. For LPS-binding activity, Des-FA-[Dab-Dab-Dab(1)]-PMB and Des-FA-[Arg-Arg-Arg(1)]-PMB showed activity comparable to PMB, while Des-FA-[Ala-Ala-Ala(1)]-PMB showed very low activity. Reduced acute toxicity of Des-FA-[Dap(1)]-PMB and Des-FA-[Trp(1)]-PMB was demonstrated by a mouse tail intravenous administration test, with LD(50) values of 23.5 and 19.0 micromol/kg, respectively, in contrast to PMB (LD(50), 4.8 micromol/kg).
