Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on <i>E. coli</i>
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 <i>E...
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MDPI AG
2023-07-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/7/1155 |
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| author | Martin Jakubec Fredrik G. Rylandsholm Philip Rainsford Mitchell Silk Maxim Bril’kov Tone Kristoffersen Eric Juskewitz Johanna U. Ericson John Sigurd M. Svendsen |
| author_facet | Martin Jakubec Fredrik G. Rylandsholm Philip Rainsford Mitchell Silk Maxim Bril’kov Tone Kristoffersen Eric Juskewitz Johanna U. Ericson John Sigurd M. Svendsen |
| author_sort | Martin Jakubec |
| collection | DOAJ |
| description | 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 <i>E. coli</i> 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). |
| first_indexed | 2024-03-11T01:15:59Z |
| format | Article |
| id | doaj.art-c79465dba642485ea21be3f218fd2be1 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T01:15:59Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-c79465dba642485ea21be3f218fd2be12023-11-18T18:32:12ZengMDPI AGBiomolecules2218-273X2023-07-01137115510.3390/biom13071155Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on <i>E. coli</i>Martin Jakubec0Fredrik G. Rylandsholm1Philip Rainsford2Mitchell Silk3Maxim Bril’kov4Tone Kristoffersen5Eric Juskewitz6Johanna U. Ericson7John Sigurd M. Svendsen8Department of Chemistry, Faculty of Science and Technology, UiT the Arctic University of Norway, 9019 Tromsø, NorwayDepartment of Chemistry, Faculty of Science and Technology, UiT the Arctic University of Norway, 9019 Tromsø, NorwayDepartment of Chemistry, Faculty of Science and Technology, UiT the Arctic University of Norway, 9019 Tromsø, NorwayDepartment of Chemistry, Faculty of Science and Technology, UiT the Arctic University of Norway, 9019 Tromsø, NorwayDepartment of Pharmacy, Faculty of Health Sciences, UiT the Arctic University of Norway, 9019 Tromsø, NorwayDepartment of Chemistry, Faculty of Science and Technology, UiT the Arctic University of Norway, 9019 Tromsø, NorwayDepartment of Medical Biology, Faculty of Health Sciences, UiT the Arctic University of Norway, 9019 Tromsø, NorwayDepartment of Medical Biology, Faculty of Health Sciences, UiT the Arctic University of Norway, 9019 Tromsø, NorwayDepartment of Chemistry, Faculty of Science and Technology, UiT the Arctic University of Norway, 9019 Tromsø, NorwayAntimicrobial 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 <i>E. coli</i> 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).https://www.mdpi.com/2218-273X/13/7/1155AMPSPRNMRliposomesLPSlipid binding |
| spellingShingle | Martin Jakubec Fredrik G. Rylandsholm Philip Rainsford Mitchell Silk Maxim Bril’kov Tone Kristoffersen Eric Juskewitz Johanna U. Ericson John Sigurd M. Svendsen Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on <i>E. coli</i> Biomolecules AMP SPR NMR liposomes LPS lipid binding |
| title | Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on <i>E. coli</i> |
| title_full | Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on <i>E. coli</i> |
| title_fullStr | Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on <i>E. coli</i> |
| title_full_unstemmed | Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on <i>E. coli</i> |
| title_short | Goldilocks Dilemma: LPS Works Both as the Initial Target and a Barrier for the Antimicrobial Action of Cationic AMPs on <i>E. coli</i> |
| title_sort | goldilocks dilemma lps works both as the initial target and a barrier for the antimicrobial action of cationic amps on i e coli i |
| topic | AMP SPR NMR liposomes LPS lipid binding |
| url | https://www.mdpi.com/2218-273X/13/7/1155 |
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