Multiple Roles of Cu(II) in Catalyzing Hydrolysis and Oxidation of β-Lactam Antibiotics.

Abstract

The widely used β-lactam antibiotics such as penicillins and cephalosporins are known to be susceptible to CuII-catalyzed hydrolysis at their four-membered β-lactam ring. However, this study elucidates that CuII can in fact play multiple roles in promoting the hydrolysis and/or oxidation of β-lactam antibiotics under environmental aquatic conditions (pH 5.0-9.0 and 22 °C), depending on β-lactams' structural characteristics and solution pH. Most significantly, the β-lactam antibiotics that contain a phenylglycine primary amine group on the side chain can undergo direct oxidation by CuII via this functional group. On the other hand, the β-lactam ring of penicillins is susceptible to CuII-catalyzed hydrolysis, followed by oxidation of the hydrolysis product by CuII. In contrast, the β-lactam ring of cephalosporins is susceptible to CuII-catalyzed hydrolysis only. Solution pH influences the CuII-promoted transformation by affecting the β-lactam and CuII complexation through protonation/deprotonation of critical organic functional groups. When CuII acts as an oxidant to promote the transformation of β-lactam antibiotics to yield CuI, the overall role of CuII appears catalytic if the reaction occurs under ambient atmospheric condition, due to quick oxidation of CuI by oxygen to regenerate CuII. Compared to earlier literature that largely assumed only the hydrolytic catalyst role of CuII in promoting degradation of β-lactam antibiotics, the oxidative roles of CuII identified by this study mark important contributions to a more accurate mechanistic understanding.