Solid-phase synthesis and in vitro biological activity of a Thr4→Ser4 analog of daptomycin. Issue 23 (1st December 2015)

• Record Type: Journal Article
• Authors: Lohani, Chuda Raj; Taylor, Robert; Palmer, Michael; Taylor, Scott D.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 23(2015)
• Page Start: 5490
• Page End: 5494
• Publication Date: 2015-12-01
• Subjects: Antibiotics -- Daptomycin -- Peptide synthesis -- Cyclic peptide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.10.072
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.