Cardiolipin prevents membrane translocation and permeabilization by daptomycin

Area of Science:

• Microbiology
• Biochemistry
• Molecular Biology

Background:

• Daptomycin is a crucial antibiotic for treating Gram-positive bacterial infections.
• Bacterial resistance to daptomycin is a growing clinical concern.
• Increased cardiolipin content in bacterial membranes is linked to daptomycin resistance.

Purpose of the Study:

• To investigate the direct inhibitory effect of cardiolipin on daptomycin-induced membrane permeabilization.
• To elucidate the mechanism by which cardiolipin mediates bacterial resistance to daptomycin.

Main Methods:

• Liposome model system to mimic bacterial membranes.
• Varying concentrations of cardiolipin and phosphatidylglycerol.
• Analysis of daptomycin oligomerization and pore formation.

Main Results:

• Cardiolipin at 10-20% molar fractions inhibited daptomycin pore formation and translocation.
• Daptomycin formed smaller oligomers (tetramers) in the presence of cardiolipin.
• Proposed daptomycin pore structure involves two aligned tetramers.

Conclusions:

• Cardiolipin directly inhibits daptomycin membrane permeabilization by preventing tetramer translocation.
• This mechanism explains cardiolipin-mediated daptomycin resistance.
• Provides novel insights into daptomycin's antibiotic action.