R. Michael Molloy

Kinetics of the Aspartyl Transpeptidation of Daptomycin, a Novel Lipopeptide Antibiotic

Two degradation products of the lipopeptide antibiotic, daptomycin, were identified and the reaction pathway and kinetics were delineated in aqueous solution at 60°C, pH range 3 to 8 and ionic strength 0.01. The degradation products were 1) a succinimido intermediate (anhydro-daptomycin) formed by attack of side-chain carbonyl on the peptide-bond nitrogen in the asp–gly sequence and 2) a β-asp daptomycin isomer formed by rehydration of the anhydrodaptomycin succinimide. This aspartyl transpeptidation pathway was found to be reversible. Formation of the anhydrodaptomycin from either daptomycin or β-asp daptomycin was pH dependent but the pH–rate profiles for anhydrodaptomycin formation were not mechanistically interpretable. The pH–rate profiles for the formation of daptomycin or β-asp daptomycin from the anhydrodaptomycin were linear with slopes = 1, which is consistent with nucleophilic hydroxide ion attack of the succinimido intermediate at either the α-carbonyl, giving rise to the β-asp daptomycin, or the β-carbonyl, giving rise to daptomycin.

Isolation and characterization of 4-epi-vancosamine

Abstract Methanolysis of glycopeptides from the A82846 complex with 1.5 N HCl in methanol gives the 2,3,6-trideoxy amino sugar 4- epi -vancosamine, 1 ; this is the first isolation of 1 from a natural product. The structure elucidation is based on NMR studies of the N , O -dibenzoyl methyl glycoside anomers 2 and 3 .