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Membranolytic Mechanism of Amphiphilic Antimicrobial β-Stranded [KL]$_n$ Peptides

Schweigardt, Fabian 1; Strandberg, Erik 2; Wadhwani, Parvesh 2; Reichert, Johannes 2; Bürck, Jochen 2; Cravo, Haroldo L. P.; Burger, Luisa 2; Ulrich, Anne S. 1,2
1 Institut für Organische Chemie (IOC), Karlsruher Institut für Technologie (KIT)
2 Institut für Biologische Grenzflächen (IBG), Karlsruher Institut für Technologie (KIT)

Abstract:

Amphipathic peptides can act as antibiotics due to membrane permeabilization. KL peptides with the repetitive sequence [Lys-Leu]$_n$-NH$_2$ form amphipathic β-strands in the presence of lipid bilayers. As they are known to kill bacteria in a peculiar length-dependent manner, we suggest here several different functional models, all of which seem plausible, including a carpet mechanism, a β-barrel pore, a toroidal wormhole, and a β-helix. To resolve their genuine mechanism, the activity of KL peptides with lengths from 6–26 amino acids (plus some inverted LK analogues) was systematically tested against bacteria and erythrocytes. Vesicle leakage assays served to correlate bilayer thickness and peptide length and to examine the role of membrane curvature and putative pore diameter. KL peptides with 10–12 amino acids showed the best therapeutic potential, i.e., high antimicrobial activity and low hemolytic side effects. Mechanistically, this particular window of an optimum β-strand length around 4 nm (11 amino acids × 3.7 Å) would match the typical thickness of a lipid bilayer, implying the formation of a transmembrane pore. Solid-state $^{15}$N- and $^{19}$F-NMR structure analysis, however, showed that the KL backbone lies flat on the membrane surface under all conditions. ... mehr


Verlagsausgabe §
DOI: 10.5445/IR/1000151640
Veröffentlicht am 20.10.2022
Originalveröffentlichung
DOI: 10.3390/biomedicines10092071
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Zitationen: 1
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Biologische Grenzflächen (IBG)
Institut für Organische Chemie (IOC)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2022
Sprache Englisch
Identifikator ISSN: 2227-9059
KITopen-ID: 1000151640
HGF-Programm 47.14.01 (POF IV, LK 01) Molekular Information Processing in Cellular Systems
Erschienen in Biomedicines
Verlag MDPI
Band 10
Heft 9
Seiten Art.-Nr.: 2071
Bemerkung zur Veröffentlichung Gefördert durch den KIT-Publikationsfonds
Vorab online veröffentlicht am 24.08.2022
Schlagwörter cationic antimicrobial peptides, length dependent activity, antimicrobial activity, hemolysis, vesicle leakage, solid-state 31P-, 15N- and 19F-NMR, β-stranded peptides, β-sheets, structure and orientation of peptides in membranes
Nachgewiesen in Web of Science
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