Antibiotic resistance continues to be a major threat to public health. β-lactamases mediate resistance toward β-lactam antibiotics through hydrolysis of the β-lactam ring. To circumvent antibiotic hydrolysis, β-lactamase inhibitors (BLIs) have been developed to block the β-lactamase so that the antibiotic can reach its enzyme target in the cell wall. Diazabicyclooctanes (DBOs; avibactam, relebactam) are a new class of BLI that reversibly inhibit class C β-lactamases, which are not inhibited by older BLIs. To further elucidate the interaction between class C β-lactamases and DBOs, the x-ray crystal structure of DHA-1, a plasmid-based class C enzyme, was determined to 1.75 Å resolution for apo DHA-1 and the relebactam/DHA-1 complex. These structures were compared with the existing structures of class C β-lactamases bound to avibactam and relebactam. This work represents the first crystal structures of DHA-1, and the second crystal structure to include relebactam (MK-7655), which is currently in Phase III clinical trials.

Interaction of diazabicyclooctane β-lactamase inhibitors with class C β-lactamases

2019 Spring National Meeting

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