Aggregation-State Dynamics Drive Double Cooperativity Between Antimicrobial Peptides LL-37 and HNP1

Area of Science:

• Biochemistry
• Molecular Biology
• Antimicrobial Research

Background:

• Antimicrobial resistance necessitates novel therapeutic strategies.
• LL-37 and HNP1 peptides exhibit a synergistic effect, enhancing antimicrobial activity and reducing host cell toxicity.
• The underlying molecular mechanisms of this cooperative effect remain largely unexplored.

Purpose of the Study:

• To elucidate the molecular mechanism behind the synergistic antimicrobial activity of LL-37 and HNP1.
• To investigate how peptide aggregation influences membrane toxicity and cell fate.
• To explore the role of lipid composition in regulating peptide aggregation and selective membrane disruption.

Main Methods:

• Total Internal Reflection Fluorescence (TIRF) microscopy
• Förster Resonance Energy Transfer (FRET)
• Nuclear Magnetic Resonance (NMR) spectroscopy
• Molecular Dynamics (MD) simulations

Main Results:

• The cooperative effect is attributed to the dynamic assembly and disassembly of LL-37/HNP1 aggregates.
• Peptide aggregation state directly correlates with membrane toxicity, influencing cell fate.
• Hydrophobic interactions between LL-37 and HNP1 drive peptide aggregation.
• Anionic lipids in membranes are crucial for disaggregating peptides, restoring antimicrobial function.
• This lipid-dependent regulation enables selective destruction of bacterial membranes while sparing eukaryotic cells.

Conclusions:

• The dynamic aggregation of LL-37 and HNP1 is the key to their synergistic antimicrobial action and reduced cytotoxicity.
• Lipid composition acts as a critical regulator, enabling targeted membrane disruption.
• This mechanism offers a promising avenue for developing advanced antibiotics against resistant bacteria.