Relative inhibitory activities of the broad-spectrum β-lactamase inhibitor xeruborbactam in comparison with taniborbactam against metallo-β-lactamases produced in Escherichia coli and Pseudomonas aeruginosa

• Published in: Antimicrobial agents and chemotherapy 2024-05, Vol.68 (6), p.e0157023
• Main Authors: Le Terrier, Christophe, Freire, Samanta, Viguier, Clément, Findlay, Jacqueline, Nordmann, Patrice, Poirel, Laurent
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Antimicrobial Chemotherapy; beta-Lactamase Inhibitors - pharmacology; beta-Lactamases - genetics; beta-Lactamases - metabolism; Borinic Acids; Carboxylic Acids; Cefepime - pharmacology; Ceftazidime - pharmacology; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli - genetics; Mechanisms of Resistance; Meropenem - pharmacology; Microbial Sensitivity Tests; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - enzymology; Pseudomonas aeruginosa - genetics
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/aac.01570-23

Xeruborbactam is a newly developed β-lactamase inhibitor designed for metallo-β-lactamases (MBLs). This study assessed the relative inhibitory properties of this novel inhibitor in comparison with another MBL inhibitor, namely taniborbactam (TAN), against a wide range of acquired MBL produced either in or . As observed with taniborbactam, the combination of xeruborbactam (XER) with β-lactams, namely, ceftazidime, cefepime and meropenem, led to significantly decreased MIC values for a wide range of B1-type MBL-producing , including most recombinant strains producing NDM, VIM, IMP, GIM-1, and DIM-1 enzymes. Noteworthily, while TAN-based combinations significantly reduced MIC values of β-lactams for MBL-producing recombinant strains, those with XER were much less effective. We showed that this latter feature was related to the MexAB-OprM efflux pump significantly impacting MIC values when testing XER-based combinations in . The relative inhibitory concentrations (IC values) were similar for XER and TAN against NDM and VIM enzymes. Noteworthily, XER was effective against NDM-9, NDM-30, VIM-83, and most of IMP enzymes, although those latter enzymes were considered resistant to TAN. However, no significant inhibition was observed with XER against IMP-10, SPM-1, and SIM-1 as well as the representative subclass B2 and B3 enzymes, PFM-1 and AIM-1. The determination of the constant inhibition ( ) of XER revealed a much higher value against IMP-10 than against NDM-1, VIM-2, and IMP-1. Hence, IMP-10 that differs from IMP-1 by a single amino-acid substitution (Val67Phe) can, therefore, be considered resistant to XER.