Structures of FOX-4 Cephamycinase in Complex withTransition-State Analog Inhibitors

Boronic acid transition-state analog inhibitors (BATSIs) are partners with &beta
lactam antibiotics for the treatment of complex bacterial infections. Herein, microbiological, biochemical, and structural findings on four BATSIs with the FOX-4 cephamycinase, a class C &beta
lactamase that rapidly hydrolyzes cefoxitin, are revealed. FOX-4 is an extended-spectrum class C cephalosporinase that demonstrates conformational flexibility when complexed with certain ligands. Like other &beta
lactamases of this class, studies on FOX-4 reveal important insights into structure&ndash
activity relationships. We show that SM23, a BATSI, shows both remarkable flexibility and affinity, binding similarly to other &beta
lactamases, yet retaining an IC50 value &lt
0.1 &mu
M. Our analyses open up new opportunities for the design of novel transition-state analogs of class C enzymes.