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Daptomycin Pore Formation Is Restricted by Lipid Acyl Chain Composition
Robert Taylor1, David Beriashvili1, Scott Taylor1
1Department of Chemistry, University of Waterloo , Waterloo, Ontario N2L 3G1, Canada.
Abstract:
Daptomycin is a calcium-dependent lipopeptide antibiotic that is used clinically against various Gram-positive pathogens. It acts on bacterial cell membranes, whose susceptibility varies with the content of phosphatidylglycerol (PG). Some studies have reported that daptomycin permeabilizes and depolarizes bacterial cell membranes, while others have found no evidence of membrane permeabilization and thus proposed different mechanisms of antibacterial action. Divergent observations have also been reported regarding the effect of daptomycin on model membranes, which were found to be permeabilized nonselectively, selectively for small cations, or not at all. While these diverging model studies did consider the functional roles of different lipid head groups, they assumed that the acyl chains were interchangeable. We here show this assumption to be erroneous. In equimolar mixtures of PG and phosphatidylcholine (PC), dimyristoyl lipids support membrane permeabilization, whereas dioleyl and palmitoleyl lipids do not, even though daptomycin does bind to and form oligomers on all of these membranes. These observations help reconcile some of the discrepant findings in the literature.
Insights
Daptomycin
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Daptomycin is a lipopeptide antibiotic targeting Gram-positive bacteria.
- Its mechanism involves interaction with bacterial cell membranes, influenced by phosphatidylglycerol (PG).
- Conflicting reports exist regarding daptomycin's membrane permeabilization effects and its action on model membranes.
Purpose of the Study:
- To investigate the role of lipid acyl chain composition in daptomycin's membrane interaction.
- To reconcile divergent findings on daptomycin's mechanism of action in model membrane systems.
Main Methods:
- Utilized model membranes composed of phosphatidylglycerol (PG) and phosphatidylcholine (PC) with varying acyl chain lengths (dimyristoyl, dioleyl, palmitoleyl).
- Assessed daptomycin binding and oligomerization on these membranes.
- Evaluated membrane permeabilization in response to daptomycin.
Main Results:
- Daptomycin binds to and forms oligomers on all tested model membranes.
- Membrane permeabilization by daptomycin was observed only with dimyristoyl lipids in equimolar PG:PC mixtures.
- Dioleyl and palmitoleyl lipids, despite supporting daptomycin binding, did not lead to membrane permeabilization.
Conclusions:
- The acyl chain composition of lipids significantly impacts daptomycin-induced membrane permeabilization.
- The assumption of acyl chain interchangeability in model membrane studies of daptomycin is incorrect.
- Acyl chain properties are critical for understanding daptomycin's antibacterial mechanism and reconciling conflicting literature data.
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