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
- 1 June 2017
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 61 (6)
- https://doi.org/10.1128/aac.02529-16
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.Keywords
Funding Information
- Wockhardt Ltd., Wockhardt Research Centre
- Veterans Affairs Merit Review Program (1I01BX002872, 1I01BX001974)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R21AI114508, R01AI100560, R01AI063517, R01AI072219)
- Ministerio de Economía y Competitividad (RD12/0015, RD16/0016)
This publication has 52 references indexed in Scilit:
- Pan-β-Lactam Resistance Development in Pseudomonas aeruginosa Clinical Strains: Molecular Mechanisms, Penicillin-Binding Protein Profiles, and Binding AffinitiesAntimicrobial Agents and Chemotherapy, 2012
- Antagonistic Interactions of Pseudomonas aeruginosa Antibiotic Resistance Mechanisms in Planktonic but Not Biofilm GrowthAntimicrobial Agents and Chemotherapy, 2011
- Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistanceFEMS Microbiology Reviews, 2011
- Affinity of the New Cephalosporin CXA-101 to Penicillin-Binding Proteins of Pseudomonas aeruginosaAntimicrobial Agents and Chemotherapy, 2010
- Activity of a New Cephalosporin, CXA-101 (FR264205), against β-Lactam-Resistant Pseudomonas aeruginosa Mutants Selected In Vitro and after Antipseudomonal Treatment of Intensive Care Unit PatientsAntimicrobial Agents and Chemotherapy, 2010
- Antibacterial-ResistantPseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance MechanismsClinical Microbiology Reviews, 2009
- Extended-Spectrum Cephalosporinases in Pseudomonas aeruginosaAntimicrobial Agents and Chemotherapy, 2009
- Affinity of Doripenem and Comparators to Penicillin-Binding Proteins in Escherichia coli and Pseudomonas aeruginosaAntimicrobial Agents and Chemotherapy, 2008
- Pseudomonas aeruginosa May Accumulate Drug Resistance Mechanisms without Losing Its Ability To Cause Bloodstream InfectionsAntimicrobial Agents and Chemotherapy, 2007
- Stepwise Upregulation of thePseudomonas aeruginosaChromosomal Cephalosporinase Conferring High-Level β-Lactam Resistance Involves Three AmpD HomologuesAntimicrobial Agents and Chemotherapy, 2006