Structures of FOX-4 cephamycinase in complex with transition-state analog inhibitors

Scott T. Lefurgy, Emilia Caselli, Magdalena A. Taracila, Vladimir N. Malashkevich, Beena Biju, Krisztina M. Papp-Wallace, Jeffrey B. Bonanno, Fabio Prati, Steven C. Almo, Robert A. Bonomo

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Boronic acid transition-state analog inhibitors (BATSIs) are partners with β-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 β-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 β-lactamases of this class, studies on FOX-4 reveal important insights into structure–activity relationships. We show that SM23, a BATSI, shows both remarkable flexibility and affinity, binding similarly to other β-lactamases, yet retaining an IC50 value < 0.1 μM. Our analyses open up new opportunities for the design of novel transition-state analogs of class C enzymes.

Original languageEnglish (US)
Article number671
Issue number5
StatePublished - May 2020


  • Boronic acid
  • Cephamycinase
  • Transition-state analog inhibitor
  • β-lactam
  • β-lactamase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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