OP0595, a new diazabicyclooctane: mode of action as a serine β-lactamase inhibitor, antibiotic and β-lactam 'enhancer'

J Antimicrob Chemother. 2015 Oct;70(10):2779-86. doi: 10.1093/jac/dkv166. Epub 2015 Jun 18.


Objectives: The production of a growing diversity of β-lactamases by Gram-negative bacteria challenges antimicrobial chemotherapy. OP0595, discovered separately by each of Meiji Seika Pharma and Fedora Pharmaceuticals, is a new diazabicyclooctane serine β-lactamase inhibitor that also acts as an antibiotic and as a β-lactamase-independent β-lactam 'enhancer'.

Methods: Inhibitory activity against serine β-lactamases and affinity for PBPs were determined using nitrocefin and Bocillin FL, respectively. MICs alone and in combination with β-lactam agents were measured according to CLSI recommendations. Morphological changes in Escherichia coli were examined by phase-contrast microscopy.

Results: IC50s of OP0595 for class A and C β-lactamases were <1000 nM, with covalent binding demonstrated to the active-site serine of CTX-M-44 and AmpC enzymes. OP0595 also had direct antibiotic activity against many Enterobacteriaceae, associated with inhibition of PBP2 and conversion of the bacteria into spherical forms. Synergy between OP0595 and β-lactam agents was seen against strains producing class A and C β-lactamases vulnerable to inhibition. Lastly, OP0595 lowered the MICs of PBP3-targeted partner β-lactam agents for a non-β-lactamase-producing E. coli mutant that was resistant to OP0595 itself, indicating β-lactamase-independent 'enhancer'-based synergy.

Conclusions: OP0595 acts in three ways: (i) as an inhibitor of class A and C β-lactamases, covalently binding at their active sites; (ii) as an antibacterial, by inhibiting PBP2 of several Enterobacteriaceae; and (iii) as an 'enhancer' of β-lactam agents that bind to other PBPs besides PBP2 for several Enterobacteriaceae. OP0595 has considerable potential to overcome resistance when it is combined with various β-lactam agents.

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / pharmacology*
  • Catalytic Domain
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Escherichia coli / genetics
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Conformation
  • beta-Lactamase Inhibitors / chemistry
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamases / chemistry
  • beta-Lactamases / metabolism
  • beta-Lactams / chemistry
  • beta-Lactams / pharmacology*


  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Lactams
  • OP0595
  • beta-Lactamase Inhibitors
  • beta-Lactams
  • beta-Lactamases