Cardiolipin Prevents Membrane Translocation and Permeabilization by Daptomycin

• DOI: 10.1074/jbc.m114.554444
• Publication Date: 2014-03-11T00:13:31Z
• Authors: TianHua Zhang; Jawad K. Muraih; Nasim Tishbi; Jennifer Herskowitz; Rachel L. Victor; Jared Silverman; Stephanie Uwumare...; Scott D. Taylor; Michael Palmer; Evan Mintzer
• Keywords: Daptomycin; Phosphatidylglycerol; Lipopeptide

Daptomycin is an acidic lipopeptide antibiotic that, in the presence of calcium, forms oligomeric pores on membranes containing phosphatidylglycerol. It clinically used against various Gram-positive bacteria such as Staphylococcus aureus and Enterococcus species. Genetic studies have indicated that increased content cardiolipin bacterial membrane may contribute to resistance drug. Here, we a liposome model demonstrate directly inhibits permeabilization by daptomycin. When added at molar fractions 10 or 20% phosphatidylglycerol, daptomycin no longer translocates inner leaflet. Under same conditions, continues form oligomers; however, these oligomers contain only close four subunits, which approximately half many observed without cardiolipin. The collective findings lead us propose pore consists two aligned tetramers opposite leaflets prevents translocation leaflet, thereby forestalling formation complete, octameric pores. Our suggest possible mechanism mediate daptomycin, they provide new insights into action mode this important antibiotic.