Inhibitor Affinity Differs among Clinical Variants of IMP Metallo-β-Lactamases: Analysis and Implications for...

Area of Science:

• Biochemistry
• Microbiology
• Drug Discovery

Background:

• β-Lactam-resistant bacterial infections pose a global health threat.
• Metallo-β-lactamases (MBLs) are key enzymes conferring resistance by hydrolyzing β-lactam antibiotics.
• Imipenemase (IMP) is a clinically significant MBL, with variants like IMP-78 showing enhanced carbapenemase activity.

Purpose of the Study:

• To investigate the inhibition mechanisms of two MBL inhibitors, RPX 7546 and D-CS319, against IMP-1 and its variant IMP-78.
• To understand how enzyme evolution in IMP-78 affects inhibitor efficacy.
• To assess the potential of these inhibitors for combating MBL-mediated resistance.

Main Methods:

• Combination of analytical and biochemical experiments.
• In silico modeling to elucidate inhibition mechanisms.
• Comparative analysis of inhibitor activity against IMP-1 and IMP-78.

Main Results:

• RPX 7546 demonstrated reduced efficacy against IMP-78 compared to IMP-1.
• D-CS319 exhibited consistent and effective inhibition against both IMP-1 and IMP-78.
• Differences in inhibitor effectiveness correlate with the evolutionary adaptations of IMP-78.

Conclusions:

• D-CS319 shows promise as a broad-spectrum MBL inhibitor effective against both wild-type and variant enzymes.
• RPX 7546's efficacy is influenced by enzyme variant-specific structural changes.
• Further research into MBL inhibitors targeting enzyme variants is crucial for clinical applications.