Membrane-Active Cyclic Amphiphilic Peptides: Broad-Spectrum Antibacterial Activity Alone and in Combination with Antibiotics

We designed a library of 24 cyclic peptides containing
arginine
(R) and tryptophan (W) residues in a sequential manner [RnWn] (n = 2–7) to study the impact of the hydrophilic/hydrophobic
ratio, charge, and ring size on the antibacterial activity against
Gram-positive and Gram-negative strains. Among peptides, 5a and 6a demonstrated the highest antimicrobial activity.
In combination with 11 commercially available antibiotics, 5a and 6a showed remarkable synergism against a large
panel of resistant pathogens. Hemolysis (HC50 = 340 μg/mL)
and cell viability against mammalian cells demonstrated the selective
lethal action of 5a against bacteria over mammalian cells.
Calcein dye leakage and scanning electron microscopy studies revealed
the membranolytic effect of 5a. Moreover, the stability
in human plasma (t1/2 = 3 h) and the negligible
ability of pathogens to develop resistance further reflect the potential
of 5a for further development as a peptide-based antibiotic.