Journal Article

PUBDB-2025-03968

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Daptomycin membrane activity is modulated by the localized interplay between calcium ions and phospholipids in monolayers and bilayers containing a lysyl-phosphatidylglycerol analogue

Hoernke, M. (First author)Extern* ; Shi, S. ; Hubbard, A. T. M. ; Geringer, N. ; Strati, F.Extern*CSSB* ; Shen, C.Extern*DESY* ; Wölk, C. (Corresponding author)Extern* ; Harvey, R. D. (Corresponding author)Extern*

2025
Elsevier Amsterdam

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Please use a persistent id in citations: doi:10.1016/j.bbamem.2025.184452

Abstract: Using the stable synthetic analogue 3-aza-dehydroxylysyl-phosphatidylglycerol (3adLPG), the putative role of native staphylococcal LPG in inhibiting the antibiotic daptomycin from binding to its target phosphatidylglycerol (PG), was investigated with respect to interfacial interactions between these lipids, daptomycin, and calcium ions. The influence of lipid monolayer/bilayer composition and interfacial ion concentrations upon the structure and integrity of model membranes were probed after daptomycin challenge using a combination of surface x-ray scattering techniques and fluorescence assays. In models representing the membrane composition of the daptomycin susceptible phenotype consisting of PG/3adLPG in a 7:3 M ratio, calcium ions drive the formation of two separate phases; Ca2+ cross-linked PG/PG pairs and PG/3adLPG ion pairs. Daptomycin is able to bind directly to the lipids in the PG/PG phase and increases the amount of interfacial Ca2+ ions to a level sufficient to displace 3adLPG from ion pairs with PG, and thus binds to its target PG. In bilayers with mixed chain lipids, daptomycin leads to pronounced membrane perturbations and enhanced permeability. Sequestering all of the available PG into PG/3adLPG ion pairs, therefore, would represent a putative daptomycin non-susceptible membrane. Daptomycin binding and the extent of subsequent lipid structural changes are reduced in these membranes. This implies that in bacteria, native LPG biosynthesis would need to ensure either an equivalence or an excess in relation to membrane PG content, in order for this mechanism alone to significantly contribute to daptomycin resistance.

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Contributing Institute(s):

1. DOOR-User (DOOR ; HAS-User)
2. Experimentebetreuung PETRA III (FS-PET-D)

Research Program(s):

1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)
2. FS-Proposal: I-20190426 (I-20190426) (I-20190426)
3. DFG project G:(GEPRIS)415894560 - Polymer-induzierte endosomale Freisetzung für drug delivery: die mechanistische Verknüpfung von pH-induzierter Polymerbindung, Leakage, Fusion und anderem physikalisch-chemischen Membranverhalten (415894560) (415894560)
4. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P08 (PETRA III)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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