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Detergent-type membrane fragmentation by MSI-78, MSI-367, MSI-594, and MSI-843 antimicrobial peptides and inhibition
Dong-Kuk Lee1, Anirban Bhunia1,2, Samuel A Kotler1
1†Biophysics and Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, United States.
Abstract:
Multidrug resistance against the existing antibiotics is becoming a global threat, and any potential drug that can be designed using cationic antimicrobial peptides (AMP) could be an alternate solution to alleviate this existing problem. The mechanism of action of killing bacteria by an AMP differs drastically in comparison to that of small molecule antibiotics. The main target of AMPs is to interact with the lipid bilayer of the cell membrane and disrupt it to kill bacteria. Consequently, the modes of membrane interaction that lead to the selectivity of an AMP are very important to understand. Here, we have used different membrane compositions, such as negatively charged, zwitterionic, or mixed large unilamellar vesicles (LUVs), to study the interaction of four different synthetically designed cationic, linear antimicrobial peptides: MSI-78 (commercially known as pexiganan), MSI-367, MSI-594, and MSI-843. Our solid-state nuclear magnetic resonance (NMR) experiments confirmed that the MSI peptides fragmented LUVs through a detergent-like carpet mechanism depending on the amino acid sequence of the MSI peptide and/or the membrane composition of LUVs. Interestingly, the fragmented lipid aggregates such as SUVs or micelles are sufficiently small to produce an isotropic peak in the (31)P NMR spectrum. These fragmented lipid aggregates contain only MSI peptides bestowed with lipid molecules as confirmed by NMR in conjunction with circular dichroism spectroscopy. Our results also demonstrate that cholesterol, which is present only in the eukaryotic cell membrane, inhibits the MSI-induced fragmentation of LUVs, suggesting that the MSI peptides can discriminate the bacteria and the eukaryotic cell membranes, and this selectivity could be used for further development of novel antibiotics.
Insights
Cationic antimicrobial peptides (AMPs) offer a novel approach to combat antibiotic resistance by disrupting bacterial cell membranes. Studies show these peptides fragment membranes selectively, sparing eukaryotic cells, paving the way for new antibiotic development.
Area of Science:
- Biochemistry
- Molecular Biology
- Antimicrobial Research
Background:
- Multidrug resistance to existing antibiotics is a growing global health crisis.
- Cationic antimicrobial peptides (AMPs) present a promising alternative therapeutic strategy.
- Understanding AMPs' membrane interaction mechanisms is crucial for developing selective antimicrobial agents.
Purpose of the Study:
- To investigate the membrane interaction and fragmentation mechanisms of four synthetic cationic AMPs (MSI-78, MSI-367, MSI-594, MSI-843).
- To determine how varying lipid compositions of large unilamellar vesicles (LUVs) affect AMP-membrane interactions.
- To assess the selectivity of these AMPs towards bacterial versus eukaryotic cell membranes.
Main Methods:
- Solid-state nuclear magnetic resonance (NMR) spectroscopy to analyze peptide-lipid interactions and membrane structural changes.
- Circular dichroism (CD) spectroscopy to confirm the composition of fragmented lipid aggregates.
- Utilized LUVs with diverse compositions (negatively charged, zwitterionic, mixed) to mimic different membrane environments.
Main Results:
- The synthetic MSI peptides fragmented LUVs via a detergent-like carpet mechanism, influenced by peptide sequence and LUV composition.
- Fragmented lipid aggregates (SUVs, micelles) containing both peptides and lipids were formed, evidenced by (31)P NMR and CD spectroscopy.
- Cholesterol, a component of eukaryotic membranes, inhibited peptide-induced LUV fragmentation, indicating selective membrane interaction.
Conclusions:
- The studied cationic AMPs exhibit a detergent-like mechanism for disrupting bacterial membranes.
- The observed selectivity, particularly the inhibition by cholesterol, suggests potential for developing targeted antibiotics with reduced host toxicity.
- These findings support the development of novel antimicrobial therapies based on AMPs to address antibiotic resistance.
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