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.
Jung
David
D
Department of Microbiology and Immunology, University of British Columbia, 232B-2259 Lower Mall, Vancouver, BC, V6T 1Z4, Canada.
Rozek
Annett
A
Okon
Mark
M
Hancock
Robert E W
RE
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