The kinetics of the alkaline degradation of daptomycin.
The aqueous degradation of daptomycin, a lipopeptide antibiotic, was investigated as a function of substrate concentration (0.5-10.0 mM), pH (9.0-10.5), buffer concentration (0.06-0.20 M borate, glycinate, or carbonate buffers), temperature (20-50 degrees C), and ionic strength (0.1-0.8). The primary degradation pathway was determined by electrospray-mass spectroscopy (ES-MS), Fourier transform infrared (FTIR), and fluorescence spectroscopy to be hydrolysis of the ester linkage between the C-terminus (kynurenine) and the side chain of the fourth residue (threonine). The reaction was first order with respect to time; however, the reaction order with respect to substrate concentration was <1 at substrate concentrations >1 mM. Insignificant buffer effect was observed. The reaction was subject to specific base catalysis. Activation parameters were E(a) = 13.6 kcal/K.mol, DeltaH++ = 13.0 kcal/K.mol, and DeltaS++ = -19.2 eu. The positive primary salt effect was observed with negative deviation at high concentration of salt. The magnitude of the salt effect depended on salt identities in the order sodium < potassium < calcium chloride.
Muangsiri
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Division of Pharmaceutics, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA.
Kirsch
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D000468:Alkalies / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D017576:Daptomycin / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D012492:Salts; D012996:Solutions; D013500:Surface Tension; D013696:Temperature; D014867:Water
D000468:Alkalies; D000900:Anti-Bacterial Agents; D002021:Buffers; D012492:Salts; D012996:Solutions; D014867:Water; D017576:Daptomycin