Small Amphiphilic Peptides: Activity Against a Broad Range of Drug-Resistant Bacteria and Structural Insight into Membranolytic Properties

We report the synthesis and antibacterial
activities of a series
of amphiphilic membrane-active peptides composed, in part, of various
nongenetically coded hydrophobic amino acids. The lead cyclic peptides, 8C and 9C, showed broad-spectrum activity against
drug-resistant Gram-positive (minimum inhibitory concentration (MIC)
= 1.5–6.2 μg/mL) and Gram-negative (MIC = 12.5–25
μg/mL) bacteria. The cytotoxicity study showed the predominant
lethal action of the peptides against bacteria as compared with mammalian
cells. A plasma stability study revealed approximately 2-fold higher
stability of lead cyclic peptides as compared to their linear counterparts
after 24 h of incubation. A calcein dye leakage experiment revealed
the membranolytic effect of the cyclic peptides. Nuclear magnetic
resonance spectroscopy and molecular dynamics simulation studies of
the interaction of the peptides with the phospholipid bilayer provided
a solid structural basis to explain the membranolytic action of the
peptides with atomistic details. These results highlight the potential
of newly designed amphiphilic peptides as the next generation of peptide-based
antibiotics.