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

The widely used beta-lactam antibiotics such as penicillins and cephalosporins are known to be susceptible to Cu-II-catalyzed hydrolysis at their four-membered beta-lactam ring. However, this study elucidates that Cu-II can in fact play multiple roles in promoting the hydrolysis and/or oxidation of beta-lactam antibiotics under environmental aquatic conditions (pH 5.0-9.0 and 22 degrees C), depending on beta-lactams' structural characteristics and solution pH. Most significantly, the beta-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 beta-lactam ring of penicillins is susceptible to Cu-II-catalyzed hydrolysis, followed by oxidation of the hydrolysis product by Cu-II. In contrast, the beta-lactam ring of cephalosporins is susceptible to Cu-II-catalyzed hydrolysis only. Solution pH influences the Cu-II-promoted transformation by affecting the beta-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 beta-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 beta-lactam antibiotics, the oxidative roles of Cu-II identified by this study mark important contributions to a more accurate mechanistic understanding.