Since the discovery of the penicillin, β-lactam antibiotics have emerged as the preferred and most widely used antimicrobial agents. However, due to the overuse of β-lactam antibiotics, bacteria have become resistant to therapeutics. The principle mechanism by which bacteria acquire resistance is through the expression of β-lactamase enzymes. Of the four known classes of β-lactamases (A-D), the class D enzymes are the most diverse and pose a threat to the carbapenems, which are considered to be “last resort” β-lactam antibiotics. Currently, all clinically-used inhibitors fail to effectively inhibit the class D β-lactamases. The ineffective inhibition occurs because the inhibitors contain the same β-lactam ring scaffold found in β-lactam antibiotics. In order to address this serious problem, molecular docking was used to identify novel inhibitors for the class D β-lactamase OXA-24. Two commercially-available chemical fragments with K<sub>I</sub> values of less than 5 mM were discovered, and their structures, in complex with OXA<sub>-</sub>24, were determined to 1.67 Å and 1.78 Å resolution. To optimize these fragment inhibitors, analogs were tested for inhibition of OXA-24. The insights gained from the fragment inhibitors and analogs will be used to develop a new series of novel β-lactamase inhibitors.

Optimization of fragment inhibitors for the class D β-lactamase OXA-24

249th National Meeting (2015)

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