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Bioorg Med Chem Lett. 2015 Dec 1;25(23):5490-4. doi: 10.1016/j.bmcl.2015.10.072. Epub 2015 Oct 24.

Solid-phase synthesis and in vitro biological activity of a Thr4→Ser4 analog of daptomycin.

Author information

1
Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
2
Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada. Electronic address: s5taylor@sciborg.uwaterloo.ca.

Abstract

Daptomycin is a Ca(+2)-dependent cyclic lipodepsipeptide antibiotic used clinically to treat serious infections caused by Gram-positive bacteria. The recent appearance of daptomycin-resistant strains, daptomycin's lack of activity in the presence of lung surfactant, and its incompletely understood mechanism of action underscores the need for establishing detailed structure-activity relationships. Here we report a solid-phase synthesis of a daptomycin analog in which Thr4, 3-MeGlu12 and Kyn13 in daptomycin were replaced with Ser, Glu and Trp residues, respectively (Dap-S4-E12-W13). The Thr4 to Ser4 substitution was detrimental to activity, as Dap-S4-E12-W13 was at least 20-fold less active at physiological Ca(+2) concentration than Dap-E12-W13. Much of its activity could be recovered at high (100 mM) Ca(+2) concentration, suggesting that the residue at position 4 affects Ca(+2) binding and, consequently, biological activity.

KEYWORDS:

Antibiotics; Cyclic peptide; Daptomycin; Peptide synthesis

PMID:
26520664
DOI:
10.1016/j.bmcl.2015.10.072
[Indexed for MEDLINE]
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