Patrick J. Baker

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.

A82775b and a82775c, novel metabolites of an unknown fungus of the order sphaeropsidales

Compounds A82775B (1) and A82775C (2) were isolated as non-antimicrobial by-products during attempts to isolate an elusive G+, G- antibiotic from culture A82775. an unidentified mold. A82775 factors B and C are present in both the mycelium and filtered broth. The metabolites were recovered from the filtered broth by adsorption on Diaion HP-20 nonfunctionalized macroreticular resin and purified by preparative reverse phase HPLC on C18 bonded phase supports. The structure elucidation of A82775 factors B (1) and C (2) has been accomplished by spectroscopic means including COSY, NOESY, INAPT, HMQC and 2D-INADEQUATE NMR experiments.