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

The widely used β-lactam antibiotics such as penicillins and cephalosporins are known to be susceptible to Cu II -catalyzed hydrolysis at their four-membered β-lactam ring. However, this study elucidates that Cu II 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 Cu II via this functional group. On the other hand, the β-lactam ring of penicillins is susceptible to Cu II -catalyzed hydrolysis, followed by oxidation of the hydrolysis product by Cu II . In contrast, the β-lactam ring of cephalosporins is susceptible to Cu II -catalyzed hydrolysis only. Solution pH influences the Cu II -promoted transformation by affecting the β-lactam and Cu II complexation through protonation/deprotonation of critical organic functional groups. When Cu II acts as an oxidant to promote the transformation of β-lactam antibiotics to yield Cu I, the overall role of Cu II appears catalytic if the reaction occurs under ambient atmospheric condition, due to quick oxidation of Cu I by oxygen to regenerate Cu II . Compared to earlier literature that largely assumed only the hydrolytic catalyst role of Cu II in promoting degradation of β-lactam antibiotics, the oxidative roles of Cu II identified by this study mark important contributions to a more accurate mechanistic understanding.