Structural Transitions as Determinants of the Action of the Calcium-Dependent Antibiotic Daptomycin

Chem Biol. 2004 Jul;11(7):949-57. doi: 10.1016/j.chembiol.2004.04.020.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Calcium / chemistry*
  • Circular Dichroism
  • Daptomycin / chemistry*
  • Magnetic Resonance Spectroscopy
  • Membranes, Artificial
  • Molecular Structure
  • Spectrometry, Fluorescence

Substances

  • Anti-Bacterial Agents
  • Membranes, Artificial
  • Daptomycin
  • Calcium

Associated data

  • PDB/1T5M
  • PDB/1T5N