The impact of lysyl-phosphatidylglycerol on the interaction of daptomycin with model membranes.

Org Biomol Chem

Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.

Published: December 2022


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Article Abstract

Daptomycin is an important clinical antibiotic for which resistance is rising. Daptomycin resistant strains of often have increased 1,2-diacyl--3-[phospho-1-(3-lysyl(1-glycerol))] (lysyl-PG) and mutations to the proteins directly involved in the synthesis and translocation of lysyl-PG are implicated in resistance mechanisms. To study the interaction of daptomycin with lysyl-DMPG-containing model membranes a new stereospecific and regioselective synthesis of lysyl-DMPG was developed. Studies on model membranes containing lysyl-DMPG demonstrate that: (1) daptomycin is not significantly repelled by the cationic charge of lysyl-DMPG; (2) daptomycin binds less avidly to lysyl-DMPG compared to DMPG; (3) the presence of lysyl-DMPG does not impact the membrane bound backbone conformation of daptomycin in a significant way; (4) lysyl-DMPG increases oligomer formation; (5) lysyl-DMPG does not impact model membrane fluidity at lysyl-PG : PG ratios that are relevant to daptomycin resistance. The results of these studies suggest that increased lysyl-PG content does not confer resistance to daptomycin by altering membrane fluidity or reducing membrane affinity but may confer resistance by altering the structure of daptomycin oligomers.

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http://dx.doi.org/10.1039/d2ob01384cDOI Listing

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