Detergent-Type Membrane Fragmentation by MSI-78, MSI-367,
MSI-594, and MSI-843 Antimicrobial Peptides and Inhibition by Cholesterol:
A Solid-State Nuclear Magnetic Resonance Study
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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 <sup>31</sup>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