Structure–activity relationships of bacterial outer-membrane permeabilizers based on polymyxin B heptapeptides

A series of cationic cyclic heptapeptides based on polymyxin B have been synthesized for use as permeabilizers of the outer membrane of Gram-negative bacteria. Only analogs with the Dab2-d-Phe3-Leu4-Xxx5 sequence (Xxx = Dab or Orn) showed a synergistic bactericidal effect when combined with conventional antibiotics, indicating that the Dab2 residue plays a critical role in permeation of the outer membrane of Gram-negative bacteria.

Graphical abstractDab2 (Dab=l-2,4-Diaminobutyric acid) residue of Polymyxin B heptapeptide plays a critical role in permeation of the outer membrane of Escherichia coli.Figure optionsDownload full-size imageDownload as PowerPoint slide