Synthesis and evaluation of novel dual-action beta-lactamase inhibitors
In recent years, the overuse and misuse of antibiotics has led to the creation and evolution of several different bacterial defense mechanisms. One such development, the beta-lactamase enzymes, allows bacterial cells to disable an important class of antibiotics, by destroying their core structure and thus removing their ability to bind their target compounds within the cell. beta-lactamases can be subdivided into two major categories, serine enzymes and metalloenzymes. Thus far, clinically effective inhibitors have been developed for only one subclass of serine enzymes. This project focuses on the development and testing of a library of compounds designed to inhibit both serine-based and metalloenzymes. Monocylic beta-lactams with nucleophilic C4 substituents designed to be released from the structure upon enzymatic hydrolysis were synthesized. The synthesized compounds' abilities to inhibit serine enzymes (through formation of an acyl enzyme upon hydrolysis) and metalloenzymes (through zinc chelation by the released C4 substituents) were tested.