Beta-lactamases inactivate beta-lactam antibiotics, which target bacterial cell wall synthesis. Plasmid-encoded beta-lactamases have become a major public health concern due to their transmissibility across species. The Fox1-10 family, a subset of plasmid-based enzymes, is unique in that their amino acid sequences are distinct from other class C members, and they are unusually active toward cefoxitin. To determine the molecular basis of resistance, the most active family member—Fox-4—was recombinantly expressed, purified, and tested <i>in vitro </i>against a panel of boronic acid transition state inhibitors (BATSI). The x-ray crystal structure of Fox-4 was determined to 1.9 Å in the presence of two of these inhibitors, as well as cefoxitin, providing insight into the catalytic mechanism through comparison of similar enzymes complexed with BATSIs and cephamycins. Ultimately, this work will inform the design of more effective antibiotics against Class C beta-lactamases.

Fox-4 cephamycinase: Analysis of structure and function

249th National Meeting (2015)

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