Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin.
Daptomycin is a cyclic anionic lipopeptide antibiotic recently approved for the treatment of complicated skin infections (Cubicin). Its function is dependent on calcium (as Ca2+). Circular dichroism spectroscopy indicated that daptomycin experienced two structural transitions: a transition upon interaction of daptomycin with Ca2+, and a further transition upon interaction with Ca2+ and the bacterial acidic phospholipid, phosphatidyl glycerol. The Ca2+-dependent insertion of daptomycin into model membranes promoted mild and more pronounced perturbations as assessed by the increase of lipid flip-flop and membrane leakage, respectively. The NMR structure of daptomycin indicated that Ca2+ induced a conformational change in daptomycin that increased its amphipathicity. These results are consistent with the hypothesis that the association of Ca2+ with daptomycin permits it to interact with bacterial membranes with effects that are similar to those of the cationic antimicrobial peptides.
Department of Microbiology and Immunology, University of British Columbia, 232B-2259 Lower Mall, Vancouver, BC, V6T 1Z4, Canada.
David
D
Jung
Annett
A
Rozek
Mark
M
Okon
Robert E W
RE
Hancock
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry*; D002942:Circular Dichroism; D017576:Daptomycin / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008567:Membranes, Artificial; D015394:Molecular Structure; D013050:Spectrometry, Fluorescence
D000900:Anti-Bacterial Agents; D008567:Membranes, Artificial; D017576:Daptomycin; D002118:Calcium