243rd American Chemical Society (ACS) Spring 2012 National Meeting
Beta-lactam antibiotics, such as penicillin, are the biochemical key to preventing bacterial infections. As a result of the expression of four classes (A-D) of beta-lactamase enzymes, bacteria have developed increased resistance to antibiotics and continue to pose a daunting public health threat. Specifically, class D beta-lactamases are characterized by a serine nucleophile activated by an atypical carboxylated lysine which acts as the general base. Little is known about the enzymes' initial recognition of its beta-lactam substrate and the subsequent mechanistic pathway. Of the nearly 160 known Class D beta-lactamases that contribute to resistance in bacterial infections like Pseudomonas aeruginosa, OXA -1 represents a subclass exhibiting increased activity against the penicillinase-resistant beta-lactam antibiotic oxacillin. Using a mutant OXA-1 (Ser67Gly), the structure of the enzyme complexed with the hydrolyzed oxacillin product was determined to 1.2 Å resolution. This atomic-level structure provides insight into the nuances of Class D beta-lactamase mechanism.