Multifunctional host defense peptides: intracellular-targeting antimicrobial peptides

Area of Science:

• Biochemistry and Molecular Biology
• Antimicrobial Peptides
• Cellular Biology

Background:

• Cationic antimicrobial peptides (AMPs) are widely believed to exert antimicrobial effects via intracellular targets and disruption of cellular processes.
• Documented intracellular activities include inhibition of DNA/protein synthesis, protein folding, enzymatic activity, and cell wall synthesis.

Purpose of the Study:

• To critically re-evaluate the prevailing views on intracellular targeting by antimicrobial peptides.
• To assess the relative importance of intracellular targeting versus membrane disruption in AMP killing strategies.
• To explore mechanisms of spontaneous translocation across cell membranes.

Main Methods:

• Review and analysis of existing scientific literature on antimicrobial peptide mechanisms.
• Focus on studies demonstrating direct intracellular activity without receptor involvement.
• Comparative analysis of peptide properties and their effects on microbial versus mammalian cells.

Main Results:

• Few antimicrobial peptides (≤3) are convincingly shown to enter microbial cells and inhibit intracellular functions without specific receptors.
• The ability to translocate and target intracellularly is likely limited to specific peptide families, not broadly shared among all AMPs.
• Membrane disruption, potentially via pore formation or lipid interactions, appears to be a common mechanism for both microbial killing and mammalian cell penetration.

Conclusions:

• The contribution of intracellular targeting to the overall antimicrobial activity of many AMPs may be overestimated.
• Membrane disruption and differential lipid interactions are likely crucial for AMP efficacy against microbes and selectivity towards mammalian cells.
• Further research is needed to elucidate the precise mechanisms of AMP translocation and intracellular action.