A well‐defined amphipathic conformation for the calcium‐free cyclic lipopeptide antibiotic, daptomycin, in aqueous solution

Abstract

Daptomycin is a 13-residue cyclic lipopeptide with Ca 2ϩ -dependent bactericidal activity against a variety of high-risk pathogens. Ring closure in daptomycin is via an ester linkage between the side chain of-free daptomycin is reported to lack a well-defined conformation (D. Jung, A. Rozek, M. Okron, and R. E. W. Hancock, Chemistry & Biology, 2004, Vol. 11, pp. 949-957) or is suggested to populate an alternate conformation (L.-J. Ball, C. M. Goult, J. A. Donarski, J. Micklefield, and V. Ramesh, Organic & Biomolecular Chemistry, 2004, Vol. 2, pp. 1872-1878 Contract grant sponsor: CUBIST Pharmaceuticals and NIH Contract grant number: GM27616 (NIH) *We dedicate this article to the memory of Murray Goodman, a bigger-than-life peptide chemist. He pursued the science of peptide design and synthesis, structure determination, and biological activity with passion. He showed by example how warmth and scientific zeal are contagious traits that engender international liaisons in the pursuit of common goals. He will be sorely missed.

The action mechanism of daptomycin

“…39 From the findings described in section 6.3, one would expect apo-daptomycin to exist mainly as aggregates under these conditions. However, these workers reported that they avoided aggregation by adding solid daptomycin to a degassed buffer in successive small portions, each of which was allowed time to completely dissolve prior to the next addition.…”

“…This question has been studied with 1 H-NMR 36,39 and optical methods. 40 In the absence of calcium and at pH 7.4 or higher, daptomycin aggregation is minimal or absent at millimolar concentrations, whereas under acidic conditions aggregates may form at concentrations as low as 0.12-0.2 mM.…”

“…Rotondi and Gierasch also noted significant line broadening in the 1 H-NMR spectrum of 1.5 mM daptomycin at pH 5.3 upon addition of 10 mM Ca 2+ . 39 The effect of Ca 2+ on daptomycin aggregation has also been studied using ultracentrifugation. 41 With 2.5 mM of daptomycin at pH 7.0, no aggregation was observed up to 0.75 equivalents of Ca 2+ .…”

Review of surfactin chemical properties and the potential biomedical applications

“…Although there is only limited knowledge of the lipopeptide molecular mode of action, a few key properties have been described. A number of lipopeptides tend to aggregate into oligomers and micelles and can readily interact with the cytoplasmic membrane via their hydrophobic moieties [28,59]. Thus, these types of compounds with their unusual structures that act rapidly on membrane integrity rather than on other vital processes are a growing source of concern in modern medicine and might perhaps hold promise for the development of a new generation of antibiotics [60].…”

Antimicrobial Properties of MX-2401, an Expanded-Spectrum Lipopeptide Active in the Presence of Lung Surfactant

“…Daptomycin, however, exhibits a different mechanism of action, as Ca 2ϩ helps daptomycin to interact with and aggregate in the membrane (2,15,19,24), leading to membrane depolarization and eventual bacterial cell death (28). Nevertheless, the presence of Ca 2ϩ had less of an effect on the activity and secondary structure/membrane interaction of MX-2401 than on those of daptomycin, consistent with its different mechanism of action, inhibiting the biosynthesis of the cell wall and teichoic acid precursors (25).…”