Mechanism of Action and Therapeutic Potential of the β-Hairpin Antimicrobial Peptide Capitellacin from the Marine Polychaeta Capitella teleta

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.

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“…The following subculturing with 3 passages (days) in the absence of the peptide showed that their final MICs were not changed. Notably, polymyxin B rapidly induced a stable resistance and displayed a 128-fold increase in the MIC value, which corresponded well to our previous results [ 21 ]. An important factor is that abarenicins do not induce a stable resistance of E. coli MDR Cl 1057 compared to the membrane-active polymyxin B, which has a similar mechanism of action.…”

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“…After showing that GK-4 has strong antibacterial activity, we tried to further clarify its antibacterial mechanisms. As an important protective barrier for Gram-positive and Gram-negative bacteria, the bacterial cell membrane is usually the target of most AMPs [ 30 , 31 , 32 ]. In addition to the outer membrane, the cytoplasmic membrane is an important barrier in both Gram-positive and Gram-negative bacteria, PG, CL and PE are the main components of the cytoplasmic membrane, and PC mainly exists in eukaryotic cells.…”

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“…An example of this detergent like model is isoeugenol, which increases membrane fluidity, affects lipid packing, and induces membrane shape changes . Similarly, Safronova et al found that the peptide capitellacin plays its antimicrobial activity through a detergent like model. In addition, the K4 peptide (a de novo AMP) also displays a detergent like mechanism for its antimicrobial activity …”