Daptomycin Pore Formation Is Restricted by Lipid Acyl Chain Composition.

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.