2. Academic Validation
  3. The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam

The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam

  • Antimicrob Agents Chemother. 2025 Jul 2;69(7):e0029725. doi: 10.1128/aac.00297-25.
Christophe Le Terrier 1 2 3,  Salvador I Drusin 4 5,  Patrice Nordmann 1 6,  Johann Pitout 7 8 9,  Gisele Peirano 7 8,  Alejandro J Vila 4 10 11,  Diego M Moreno 4 5,  Laurent Poirel 1 6
Affiliations

Affiliations

  • 1 Medical and Molecular Microbiology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
  • 2 Division of Intensive Care, Department of Acute Care Medicine, Geneva University Hospitals, Geneva, Switzerland.
  • 3 Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
  • 4 Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Santa Fe, Argentina.
  • 5 Instituto de Química Rosario (IQUIR, CONICET-UNR), Rosario, Santa Fe, Argentina.
  • 6 Swiss National Reference Center for Emerging Antibiotic Resistance, Fribourg, Switzerland.
  • 7 Cummings School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • 8 Alberta Precision Laboratories, Calgary, Alberta, Canada.
  • 9 University of Pretoria, Pretoria, Gauteng, South Africa.
  • 10 Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Rosario, Santa Fe, Argentina.
  • 11 CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA.
PMID: 40488615 DOI: 10.1128/aac.00297-25
Abstract

Metallo-β-lactamases (MBLs) of IMP type are not inhibited by currently commercialized β-lactamase inhibitors, including taniborbactam (TAN), which inhibits only NDM- and VIM-type Enzymes. However, the development of xeruborbactam (XER), which additionally inhibits IMP Enzymes, may provide effective drug combinations such as meropenem-XER (MEM-XER) against most MBL producers. Thirty-two IMP-producing clinical gram-negative isolates were tested for MEM-XER. Susceptibility testing of β-lactams with TAN or XER at 4 or 8 µg/mL was performed. Noticeably, MEM-XER remained ineffective against all IMP-producing Pseudomonas aeruginosa isolates. By contrast, supplementation with XER significantly lowered MEM MICs for several IMP-producing Enterobacterales isolates, except for isolates and recombinant E. coli strains producing IMP-6, IMP-10, IMP-14, and IMP-26. Interestingly, IMP-59 producers showed susceptibility to both TAN- and XER-based combinations, although IMP Enzymes are not supposed to be inhibited by TAN. Determinations of 50% inhibitory concentration (IC50) values of XER showed values being >15-fold higher for IMP-6, IMP-10, IMP-14, and IMP-26 compared with IMP-1. Interestingly, the IC50 value of TAN for IMP-59 was found in the same range as that for NDM-1 (7 µM). Finally, structural analyses and molecular modeling simulations indicated that the Ser262Gly mutation in IMP-6 may alter the electronic properties of the active site, whereas the Phe residue in IMP-10 may exert a steric effect counteracting XER binding. Resistance to XER in IMP-6, IMP-10, IMP-14, and IMP-26 variants, conferring resistance to MEM-XER, might be considered a serious concern since MEM-XER will be supposed to be a salvage therapy for MBL-, and especially IMP-producing Enterobacterales infections.

Keywords

IMP; carbapenemase; metallo-beta-lactamase; xeruborbactam.

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