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

Area of Science:

• Microbiology
• Infectious Diseases
• Drug Discovery

Background:

• Metallo-β-lactamases (MBLs) are critical resistance mechanisms in Gram-negative bacteria.
• Existing β-lactamase inhibitors like taniborbactam (TAN) do not cover IMP-type MBLs.
• Xeruborbactam (XER) offers expanded coverage, including IMP enzymes, enabling novel combination therapies.

Purpose of the Study:

• To evaluate the efficacy of meropenem-xeruborbactam (MEM-XER) against clinical isolates producing IMP-type metallo-β-lactamases.
• To identify specific IMP variants and bacterial species that remain resistant to MEM-XER.
• To investigate the molecular basis for resistance to XER in certain IMP-type MBL producers.

Main Methods:

• Antimicrobial susceptibility testing of 32 IMP-producing Gram-negative isolates against MEM-XER.
• Determination of 50% inhibitory concentration (IC50) values for XER and TAN against various IMP variants.
• Structural analysis and molecular modeling to elucidate resistance mechanisms.

Main Results:

• MEM-XER was ineffective against all tested IMP-producing *Pseudomonas aeruginosa* isolates.
• XER supplementation reduced meropenem minimum inhibitory concentrations (MICs) in many *Enterobacterales* isolates, but not those producing IMP-6, IMP-10, IMP-14, and IMP-26.
• IMP-59 producers showed susceptibility to both TAN- and XER-based combinations.
• Molecular modeling suggested specific mutations (e.g., Ser262Gly in IMP-6) and residues (e.g., Phe in IMP-10) hinder XER binding.

Conclusions:

• MEM-XER demonstrates potential as a salvage therapy for certain IMP-producing *Enterobacterales* infections.
• The emergence of resistance to XER in specific IMP variants (IMP-6, IMP-10, IMP-14, IMP-26) is a significant clinical concern.
• Further research is needed to develop inhibitors effective against all MBL types, including these resistant IMP variants.