Cyclic Boronates Inhibit All Classes of β-Lactamases

Area of Science:

• Medicinal Chemistry
• Microbiology
• Structural Biology

Background:

• β-Lactamase-mediated resistance is a significant global health threat, diminishing the effectiveness of β-lactam antibiotics.
• Current inhibitors, including serine-β-lactamase (SBL) inhibitors like avibactam, are ineffective against metallo-β-lactamases (MBLs).
• The co-production of SBLs and MBLs in bacterial infections presents a major clinical challenge, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the potential of cyclic boronates as dual-action inhibitors targeting both serine- and metallo-β-lactamases.
• To evaluate the efficacy of cyclic boronates against diverse classes of β-lactamases, including clinically relevant enzymes.
• To elucidate the mechanism of inhibition by cyclic boronates through structural analysis.

Main Methods:

• Testing cyclic boronates against purified β-lactamase enzymes from all four classes (A, B, C, and D).
• Assessing the ability of cyclic boronates to restore β-lactam antibiotic activity against Gram-negative clinical isolates.
• Determining crystal structures of β-lactamase:cyclic boronate complexes to understand binding interactions.

Main Results:

• Cyclic boronates demonstrated inhibitory activity against all four classes of β-lactamases, including extended-spectrum β-lactamase CTX-M-15, AmpC, and carbapenem-hydrolyzing OXA enzymes.
• Cyclic boronates successfully potentiated the activity of β-lactams against Gram-negative bacteria expressing various β-lactamases.
• Structural studies revealed a conserved binding mode of cyclic boronates across different β-lactamase classes, suggesting a common inhibitory mechanism.

Conclusions:

• Cyclic boronates represent a promising class of compounds capable of inhibiting all major classes of β-lactamases.
• These inhibitors offer a potential solution to overcome MBL-mediated resistance and restore the utility of β-lactam antibiotics.
• The conserved binding mode supports the hypothesis that cyclic boronates mimic the transition state of β-lactamase catalysis, providing a basis for further drug development.