Abstract
Objectives: The production of a growing diversity of b-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 b-lactamase inhibitor that also acts as an antibiotic and as a b-lactamase-independent b-lactam ‘enhancer’.
Methods: Inhibitory activity against serine b-lactamases and affinity for PBPs were determined using nitrocefin and Bocillin FL, respectively. MICs alone and in combination with b-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 b-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 b-lactam agents was seen against strains producing class A and C b-lactamases vulnerable to inhibition. Lastly, OP0595 lowered the MICs of PBP3-targeted partner b-lactam agents for a non-blactamase-producing
E. coli mutant that was resistant to OP0595 itself, indicating b-lactamase-independent ‘enhancer’-based synergy.
Conclusions: OP0595 acts in three ways: (i) as an inhibitor of class A and C b-lactamases, covalently binding at their active sites; (ii) as an antibacterial, by inhibiting PBP2 of several Enterobacteriaceae; and (iii) as an ‘enhancer’ of b-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 b-lactam agents.
Methods: Inhibitory activity against serine b-lactamases and affinity for PBPs were determined using nitrocefin and Bocillin FL, respectively. MICs alone and in combination with b-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 b-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 b-lactam agents was seen against strains producing class A and C b-lactamases vulnerable to inhibition. Lastly, OP0595 lowered the MICs of PBP3-targeted partner b-lactam agents for a non-blactamase-producing
E. coli mutant that was resistant to OP0595 itself, indicating b-lactamase-independent ‘enhancer’-based synergy.
Conclusions: OP0595 acts in three ways: (i) as an inhibitor of class A and C b-lactamases, covalently binding at their active sites; (ii) as an antibacterial, by inhibiting PBP2 of several Enterobacteriaceae; and (iii) as an ‘enhancer’ of b-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 b-lactam agents.
Original language | English |
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Pages (from-to) | 2779-2786 |
Number of pages | 8 |
Journal | Journal of Antimicrobial Chemotherapy |
Volume | 70 |
Issue number | 10 |
Early online date | 18 Jun 2015 |
DOIs | |
Publication status | Published - Oct 2015 |
Keywords
- Enterobacteriaceae
- antibiotic resistance
- penicillin-binding proteins