Abstract
Among the most potent and proteolytically resistant antimicrobial peptides (AMPs) of animal origin are molecules forming a β-hairpin structure stabilized by disulfide bonds. In this study, we investigated the mechanism of action and therapeutic potential of the β-hairpin AMP from the marine polychaeta Capitella teleta, named capitellacin. The peptide exhibits a low cytotoxicity toward mammalian cells and a pronounced activity against a wide range of bacterial pathogens including multi-resistant bacteria, but the mechanism of its antibacterial action is still obscure. In view of this, we obtained analogs of capitellacin and tachyplesin-inspired chimeric variants to identify amino acid residues important for biological activities. A low hydrophobicity of the β-turn region in capitellacin determines its modest membranotropic activity and slow membrane permeabilization. Electrochemical measurements in planar lipid bilayers mimicking the E. coli membrane were consistent with the detergent-like mechanism of action rather than with binding to a specific molecular target in the cell. The peptide did not induce bacterial resistance after a 21-day selection experiment, which also pointed at a membranotropic mechanism of action. We also found that capitellacin can both prevent E. coli biofilm formation and destroy preformed mature biofilms. The marked antibacterial and antibiofilm activity of capitellacin along with its moderate adverse effects on mammalian cells make this peptide a promising scaffold for the development of drugs for the treatment of chronic E. coli infections, in particular those caused by the formation of biofilms.
Highlights
Antimicrobial peptides (AMPs) play a key role in the immune system of invertebrates and vertebrates, as well as in plants, and they are considered as prototypes of new antibiotics [1]
We performed a structure–activity relationship study of capitellacin to improve its antimicrobial activity and identify amino acid residues contributing to the low membranolytic activity and cytotoxicity of the peptide
The low cytotoxicity profile of capitellacin allowed the improvement of its selectivity through activity buildup
Summary
The rapid emergence of resistant bacteria is occurring worldwide, compromising the effectiveness of conventional antibiotics. Among all structurally diverse AMPs, β-hairpin peptides attract particular attention. Their main advantages include a broad-spectrum activity, rapid bactericidal action, low development of resistance, and increased structural stability to proteolytic degradation. Marked difference are observed between the mechanism of action of capitellacin and tachyplesin-1 despite their high structural similarity. Several proposed mechanisms of action of tachyplesin-1 are primarily related to the bacterial strain, concentration of the peptide, and time of its exposure. Despite a substantial structural homology between tachyplesin-1 and capitellacin, the basis of the differences in their mechanisms of action remains unknown and is the focus of our attention. The antibacterial, cytotoxic, and antibiofilm properties of capitellacin analogs and the ability of capitellacin to permeabilize both living bacterial cells and model systems mimicking bacterial membranes were studied
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