title: Solid-phase synthesis and in vitro biological activity of a Thr4→Ser4 analog of daptomycin.
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.
authors.affiliation: Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Chuda Raj
authors.initials: CR
authors.lastname: Lohani
authors.affiliation: Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Taylor
authors.affiliation: Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Palmer
authors.affiliation: Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada. Electronic address: s5taylor@sciborg.uwaterloo.ca.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Taylor
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001406:Bacillaceae / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D017576:Daptomycin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012694:Serine / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques; D013912:Threonine / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D013912:Threonine; D012694:Serine; D017576:Daptomycin; D002118:Calcium
keywords: Antibiotics; Cyclic peptide; Daptomycin; Peptide synthesis