Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors

Biomolecules. 2020 Apr 27;10(5):671. doi: 10.3390/biom10050671.

Abstract

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.

Keywords: boronic acid; cephamycinase; transition-state analog inhibitor; β-lactam; β-lactamase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites
  • Boronic Acids / chemistry
  • Cephalothin / analogs & derivatives*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / metabolism
  • Molecular Docking Simulation
  • Protein Binding
  • beta-Lactamases / chemistry*
  • beta-Lactamases / metabolism

Substances

  • Anti-Bacterial Agents
  • Boronic Acids
  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • fox-4 protein, E coli
  • beta-Lactamases
  • Cephalothin