Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin.

David Jung, Annett Rozek, Mark Okon, Robert E W Hancock

Department of Microbiology and Immunology, University of British Columbia, 232B-2259 Lower Mall, Vancouver, BC, V6T 1Z4, Canada.

Chemistry & biology 2004 Jul

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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.

Citation

David Jung, Annett Rozek, Mark Okon, Robert E W Hancock. Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin. Chemistry & biology. 2004 Jul;11(7):949-57