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

Morinaka, Akihiro, Tsutsumi, Yuko, Yamada, Mototsugu, Suzuki, Kenji, Watanabe, Takashi, Ida, Takao, Furuuchi, Takeshi, Inamura, Seiichi, Sakamaki, Yoshiaki, Mitsuhashi, Nakako, Mitsuhashi, Nakako, Ida, Takashi and Livermore, David ORCID: https://orcid.org/0000-0002-9856-3703 (2015) OP0595, a new diazabicyclooctane: Mode of action as a serine beta-lactamase inhibitor, antibiotic and beta-lactam 'enhancer'. Journal of Antimicrobial Chemotherapy, 70 (10). pp. 2779-2786. ISSN 0305-7453

Microsoft Word (Meiji OP0595 MOA) - Accepted Version Download (1MB)

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.

Item Type:	Article
Uncontrolled Keywords:	enterobacteriaceae,antibiotic resistance,penicillin-binding proteins
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Epidemiology and Public Health Faculty of Medicine and Health Sciences > Research Groups > Public Health and Health Services Research (former - to 2023)
Depositing User:	Pure Connector
Date Deposited:	24 Jul 2015 23:01
Last Modified:	21 Oct 2022 01:02
URI:	https://ueaeprints.uea.ac.uk/id/eprint/53794
DOI:	10.1093/jac/dkv166

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