Aromatic Diboronic Acids as Effective KPC/AmpC Inhibitors
Joanna Krajewska1, Piotr Chyży2, Krzysztof Durka3
1Department of Pharmaceutical Microbiology and Bioanalysis, Medical University of Warsaw, 02-097 Warsaw, Poland.
Molecules (Basel, Switzerland)
|November 14, 2023
Summary
Ortho-phenylenediboronic acid 3a shows strong synergy with carbapenems against KPC carbapenemases, reducing their minimum inhibitory concentrations. This compound is a promising, non-toxic scaffold for developing new inhibitors against resistant bacteria.
Area of Science:
- Medicinal Chemistry
- Organic Chemistry
- Biochemistry
Background:
- Beta-lactamase enzymes, particularly KPC-type carbapenemases, confer resistance to essential antibiotics.
- Novel inhibitors are urgently needed to combat rising antimicrobial resistance.
Purpose of the Study:
- To investigate phenylenediboronic acids and related compounds as potential inhibitors of beta-lactamases.
- To identify specific compounds and elucidate their mechanism of action against KPC carbapenemases.
Main Methods:
- Synthesis and screening of over 30 boron-containing compounds.
- Checkerboard assays to evaluate synergistic effects with carbapenems.
- Enzyme inhibition assays (nitrocefin hydrolysis) and whole-cell assays.
- Quantum mechanics/molecular mechanics (QM/MM) modeling.
Main Results:
- Ortho-phenylenediboronic acid 3a demonstrated the highest activity against KPC carbapenemases, significantly reducing carbapenem MICs.
- Synergistic effects were observed between carbapenems and compound 3a (FIC indices 0.1-0.32).
- Compound 3a was confirmed to target the KPC enzyme, with QM/MM modeling showing covalent binding to Ser70.
Conclusions:
- Ortho-phenylenediboronic acids exhibit potent synergistic activity with carbapenems against KPC-producing bacteria.
- The investigated compounds, particularly 3a, are non-toxic to human fibroblasts and represent promising scaffolds for novel KPC/AmpC inhibitor development.
Keywords:
KPC/AmpC β-lactamase inhibitorsantibacterial activityarylboronic acidsmolecular dockingtime-dependent QM/MMMore Related Videos
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