Enantiomeric amphipathic α-helical antibacterial peptides were synthesized and their biophysical and biological properties under different physiological conditions were studied. In the absence of physiological factors, the L- and D-peptides exhibited similar antimicrobial activities against a broad spectrum of bacteria, even against clinical isolates with resistance to traditional antibiotics. However, in the presence of NaCl, CaCl₂ or human serum albumin (HSA) at physiological concentrations, the enantiomers revealed bacterium-species dependent attenuations in antibacterial activity. In the presence of salts the electrostatic interaction between the peptides and the biomembrane was inhibited. Salts, especially CaCl₂ weakened the ability of the peptides to permeabilize the outer membrane of Gram-negative bacteria, as determined by a 1-N-phenylnaphthylamine uptake assay. HSA exhibited variable inhibitory effects on the activity of the peptides when incubated with different bacterial strains. The peptides showed different binding association abilities to HSA at different molar ratios, regardless of their chirality, resulting in reduced peptide biological activity. The D-peptide performed better than its L-enantiomer in all conditions tested because of its resistance to proteolysis, and may therefore represent a promising candidate for development as a therapeutic agent.
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