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 degrees 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 beta-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 beta-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 beta-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 alpha-carbonyl, giving rise to the beta-asp daptomycin, or the beta-carbonyl, giving rise to daptomycin.
Kirsch
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LE
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285.
Molloy
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RM
Debono
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M
Baker
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P
Farid
K Z
KZ
D001224:Aspartic Acid / Q000378:metabolism*; D001711:Biotransformation; D002264:Carboxylic Acids / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D017576:Daptomycin; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D010455:Peptides / Q000378:metabolism / Q000493:pharmacokinetics; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors
D002264:Carboxylic Acids; D010455:Peptides; D001224:Aspartic Acid; D017576:Daptomycin