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.
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 diazabicyclooctaneserine 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.
Authors: Krisztina M Papp-Wallace; Nhu Q Nguyen; Michael R Jacobs; Christopher R Bethel; Melissa D Barnes; Vijay Kumar; Saralee Bajaksouzian; Susan D Rudin; Philip N Rather; Satish Bhavsar; Tadiparthi Ravikumar; Prasad K Deshpande; Vijay Patil; Ravindra Yeole; Sachin S Bhagwat; Mahesh V Patel; Focco van den Akker; Robert A Bonomo Journal: J Med Chem Date: 2018-04-20 Impact factor: 7.446
Authors: Thomas F Durand-Réville; Satenig Guler; Janelle Comita-Prevoir; Brendan Chen; Neil Bifulco; Hoan Huynh; Sushmita Lahiri; Adam B Shapiro; Sarah M McLeod; Nicole M Carter; Samir H Moussa; Camilo Velez-Vega; Nelson B Olivier; Robert McLaughlin; Ning Gao; Jason Thresher; Tiffany Palmer; Beth Andrews; Robert A Giacobbe; Joseph V Newman; David E Ehmann; Boudewijn de Jonge; John O'Donnell; John P Mueller; Rubén A Tommasi; Alita A Miller Journal: Nat Microbiol Date: 2017-06-30 Impact factor: 17.745
Authors: Sarah M McLeod; Adam B Shapiro; Samir H Moussa; Michele Johnstone; Robert E McLaughlin; Boudewijn L M de Jonge; Alita A Miller Journal: Antimicrob Agents Chemother Date: 2018-01-25 Impact factor: 5.191
Authors: Bartolome Moya; Isabel M Barcelo; Sachin Bhagwat; Mahesh Patel; German Bou; Krisztina M Papp-Wallace; Robert A Bonomo; Antonio Oliver Journal: Antimicrob Agents Chemother Date: 2017-10-24 Impact factor: 5.191