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) for...
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Veröffentlicht in: | Pharmaceutical research 1989-05, Vol.6 (5), p.387-393 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0724-8741 1573-904X |
DOI: | 10.1023/A:1015927330908 |