title: 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.
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 againstPseudomonas 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 (blaVIM-2) and ST111 (blaVIM-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 (apparentKi[Kiapp] > 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 theP. aeruginosamutant 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 MDRP. aeruginosainfections, bypassing the need for MBL inhibition.
authors.affiliation: Servicio de Microbiología and Unidad de Investigación, Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain bmoya@cop.ufl.edu.
authors.forename: Bartolome
authors.initials: B
authors.lastname: Moya
authors.affiliation: Servicio de Microbiología and Unidad de Investigación, Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Barcelo
authors.affiliation: Wockhardt Research Centre, Aurangabad, India.
authors.forename: Sachin
authors.initials: S
authors.lastname: Bhagwat
authors.affiliation: Wockhardt Research Centre, Aurangabad, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Patel
authors.affiliation: Servicio de Microbiología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain.
authors.forename: German
authors.initials: G
authors.lastname: Bou
authors.affiliation: Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.|Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Krisztina M
authors.initials: KM
authors.lastname: Papp-Wallace
authors.affiliation: Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.|Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Departments of Pharmacology, Molecular Biology and Microbiology, and Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.affiliation: Servicio de Microbiología and Unidad de Investigación, Hospital Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliver
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D034242:Cyclooctanes / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D001618:beta-Lactamases / Q000378:metabolism*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D034242:Cyclooctanes; D046915:Penicillin-Binding Proteins; D010880:Piperidines; D047090:beta-Lactams; C000624484:zidebactam; D001618:beta-Lactamases
keywords: Gram-negative bacteria; PBP2 inhibition; Pseudomonas aeruginosa; WCK 5107; WCK 5153; bicyclo-acyl hydrazide; penicillin-binding proteins; time-kill curves; zidebactam; β-lactam enhancer