Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Goldilocks Dilemma: Lps Works Both As the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on E. coli

Martin Jakubec
* ORCID logo ,
Fredrik Garnås Rylandsholm
,
Philip Rainsford
ORCID logo ,
Mitchell Silk
,
Maxim Bril'kov
,
Tone Kristoffersen
,
Eric Juskewitz
ORCID logo ,
Johanna U. Ericson
,
Johan Mattias Isaksson
ORCID logo ,
John Sigurd Mjøen Svendsen
ORCID logo
Version 1 : Received: 28 June 2023 / Approved: 29 June 2023 / Online: 29 June 2023 (11:27:25 CEST)

A peer-reviewed article of this Preprint also exists.

Jakubec, M.; Rylandsholm, F.G.; Rainsford, P.; Silk, M.; Bril’kov, M.; Kristoffersen, T.; Juskewitz, E.; Ericson, J.U.; Svendsen, J.S.M. Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on E. coli. Biomolecules 2023, 13, 1155. Jakubec, M.; Rylandsholm, F.G.; Rainsford, P.; Silk, M.; Bril’kov, M.; Kristoffersen, T.; Juskewitz, E.; Ericson, J.U.; Svendsen, J.S.M. Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on E. coli. Biomolecules 2023, 13, 1155.

Abstract

Antimicrobial peptides (AMPs) are generally membrane-active compounds that physically disrupt bacterial membranes. Despite extensive research, the precise mode of action of AMPs is still a topic of great debate. This work demonstrates that the initial interaction between the Gram-negative E. coli and AMPs is driven by lipopolysaccharides (LPS) that act as kinetic barriers for the binding of AMPs to the bacterial membrane. A combination of SPR and NMR experiments provide evidence suggesting that cationic AMPs first bind to the negatively charged LPS before reaching a binding place in the lipid bilayer. In the event that the initial LPS-binding is too strong (corresponding to a low dissociation rate), the cationic AMPs cannot effectively get from the LPS to the membrane and their antimicrobial potency will thus be diminished. On the other hand, the AMPs must also be able to effectively interact with the membrane to exert its activity. The ability of the studied cyclic hexapeptides to bind LPS and to translocate into a lipid membrane is related to the nature of the cationic charge (arginine vs lysine) and to the distribution of hydrophobicity along the molecule (alternating vs clumped tryptophan).

Keywords

AMP; SPR; NRM; liposomes; LPS; lipid binding

Subject

Biology and Life Sciences, Biophysics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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