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      WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent “β-Lactam Enhancer” Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones

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          ABSTRACT

          Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against Pseudomonas aeruginosa, including multidrug-resistant (MDR) metallo-β-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal β-lactams using wild-type PAO1, MexAB-OprM-hyperproducing ( mexR), porin-deficient ( oprD), and AmpC-hyperproducing ( dacB) derivatives of PAO1, and MBL-expressing clinical strains ST175 ( bla VIM-2) and ST111 ( bla VIM-1). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent K i [ K i app] > 100 μM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 μg/ml (amdinocillin MICs > 32 μg/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 μg/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested β-lactams for each of the P. aeruginosa mutant strains. Likewise, antipseudomonal β-lactams (CLSI breakpoints), in combination with 4 or 8 μg/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. β-Lactam–WCK enhancer combinations represent a promising β-lactam “enhancer-based” approach to treat MDR P. aeruginosa infections, bypassing the need for MBL inhibition.

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          Author and article information

          Journal
          Antimicrob Agents Chemother
          Antimicrob. Agents Chemother
          aac
          aac
          AAC
          Antimicrobial Agents and Chemotherapy
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0066-4804
          1098-6596
          13 March 2017
          24 May 2017
          June 2017
          : 61
          : 6
          : e02529-16
          Affiliations
          [a ]Servicio de Microbiología and Unidad de Investigación, Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain
          [b ]Wockhardt Research Centre, Aurangabad, India
          [c ]Servicio de Microbiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
          [d ]Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA
          [e ]Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
          [f ]Departments of Pharmacology, Molecular Biology and Microbiology, and Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
          Author notes
          Address correspondence to Bartolome Moya, bmoya@ 123456cop.ufl.edu .
          [*]

          Present address: Bartolome Moya, Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics, University of Florida, College of Pharmacy, Orlando, Florida, USA.

          Citation Moya B, Barcelo IM, Bhagwat S, Patel M, Bou G, Papp-Wallace KM, Bonomo RA, Oliver A. 2017. WCK 5107 (zidebactam) and WCK 5153 are novel inhibitors of PBP2 showing potent “β-lactam enhancer” activity against Pseudomonas aeruginosa, including multidrug-resistant metallo-β-lactamase-producing high-risk clones. Antimicrob Agents Chemother 61:e02529-16. https://doi.org/10.1128/AAC.02529-16.

          Article
          PMC5444176 PMC5444176 5444176 02529-16
          10.1128/AAC.02529-16
          5444176
          28289035
          52bc2d1b-d0a6-4d62-82a6-ad80f56f80ec
          Copyright © 2017 American Society for Microbiology.

          All Rights Reserved.

          History
          : 28 November 2016
          : 21 December 2016
          : 24 February 2017
          Page count
          Figures: 7, Tables: 4, Equations: 0, References: 52, Pages: 12, Words: 7068
          Funding
          Funded by: Wockhardt Ltd., Wockhardt Research Centre
          Award Recipient : Bartolome Moya Award Recipient : Antonio Oliver
          Funded by: Veterans Affairs Merit Review Program
          Award ID: 1I01BX002872
          Award ID: 1I01BX001974
          Award Recipient : Krisztina M. Papp-Wallace Award Recipient : Robert A. Bonomo
          Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) https://doi.org/10.13039/100000060
          Award ID: R21AI114508
          Award ID: R01AI100560
          Award ID: R01AI063517
          Award ID: R01AI072219
          Award Recipient : Robert A. Bonomo
          Funded by: Ministerio de Economía y Competitividad (MINECO) https://doi.org/10.13039/501100003329
          Award ID: RD12/0015
          Award ID: RD16/0016
          Award Recipient : Bartolome Moya Award Recipient : Isabel M. Barcelo Award Recipient : Antonio Oliver
          Categories
          Mechanisms of Action: Physiological Effects
          Custom metadata
          June 2017

          time-kill curves,β-lactam enhancer,bicyclo-acyl hydrazide,PBP2 inhibition, Pseudomonas aeruginosa ,WCK 5107,WCK 5153,Gram-negative bacteria,penicillin-binding proteins,zidebactam

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