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A. Schromm, L. Paulowski, Y. Kaconis, F. Kopp, M. Koistinen, A. Donoghue, S. Keese, C. Nehls, J. Wernecke, P. Garidel, E. Sevcsik, K. Lohner, S. Sanchez-Gomez, G. Martinez-De-Tejada, K. Brandenburg, M. Brameshuber, G. Schütz, J. Andrä, T. Gutsmann:
"Cathelicidin and PMB neutralize endotoxins by multifactorial mechanisms including LPS interaction and targeting of host cell membranes";
PNAS - Proceedings of the National Academy of Sciences of the United States of America, 118 (2021), 27, e2101721118; 1 - 12.

Antimicrobial peptides (AMPs) contribute to an effective protection
against infections. The antibacterial function of AMPs depends on
their interactions with microbial membranes and lipids, such as
lipopolysaccharide (LPS; endotoxin). Hyperinflammation induced by

endotoxin is a key factor in bacterial sepsis and many other human

diseases. Here, we provide a comprehensive profile of peptide-
mediated LPS neutralization by systematic analysis of the effects
of a set of AMPs and the peptide antibiotic polymyxin B (PMB) on

the physicochemistry of endotoxin, macrophage activation, and le-

thality in mice. Mechanistic studies revealed that the host defense
peptide LL-32 and PMB each reduce LPS-mediated activation also via
a direct interaction of the peptides with the host cell. As a biophys-

ical basis, we demonstrate modifications of the structure of
cholesterol-rich membrane domains and the association of glycosyl-
phosphatidylinositol (GPI)-anchored proteins. Our discovery of a

host cell-directed mechanism of immune control contributes an im-
portant aspect in the development and therapeutic use of AMPs.

http://dx.doi.org/10.1073/pnas.2101721118

https://doi.org/10.1073/pnas.2101721118