Lateral membrane organization as target of an antimicrobial peptidomimetic compound

Adéla Melcrová, Sourav Maity, Josef Melcr, Niels A. W. Kok, Mariella Gabler, Jonne Eyden, Wenche Stensen, John S. M. Svendsen, Arnold J. M. Driessen, Siewert J. Marrink and Wouter H. Roos ()
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Adéla Melcrová: Rijksuniversiteit Groningen
Sourav Maity: Rijksuniversiteit Groningen
Josef Melcr: Rijksuniversiteit Groningen
Niels A. W. Kok: Rijksuniversiteit Groningen
Mariella Gabler: Rijksuniversiteit Groningen
Jonne Eyden: Rijksuniversiteit Groningen
Wenche Stensen: UiT Arctic University of Norway
John S. M. Svendsen: UiT Arctic University of Norway
Arnold J. M. Driessen: Rijksuniversiteit Groningen
Siewert J. Marrink: Rijksuniversiteit Groningen
Wouter H. Roos: Rijksuniversiteit Groningen

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Antimicrobial resistance is one of the leading concerns in medical care. Here we study the mechanism of action of an antimicrobial cationic tripeptide, AMC-109, by combining high speed-atomic force microscopy, molecular dynamics, fluorescence assays, and lipidomic analysis. We show that AMC-109 activity on negatively charged membranes derived from Staphylococcus aureus consists of two crucial steps. First, AMC-109 self-assembles into stable aggregates consisting of a hydrophobic core and a cationic surface, with specificity for negatively charged membranes. Second, upon incorporation into the membrane, individual peptides insert into the outer monolayer, affecting lateral membrane organization and dissolving membrane nanodomains, without forming pores. We propose that membrane domain dissolution triggered by AMC-109 may affect crucial functions such as protein sorting and cell wall synthesis. Our results indicate that the AMC-109 mode of action resembles that of the disinfectant benzalkonium chloride (BAK), but with enhanced selectivity for bacterial membranes.

Date: 2023
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DOI: 10.1038/s41467-023-39726-5

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