Will morphing boron-based inhibitors beat the β-lactamases?

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Drug Discovery

Background:

• Antibacterial resistance, particularly from β-lactamases, compromises the efficacy of β-lactam antibiotics.
• Current inhibitors are susceptible to evolved β-lactamases and ineffective against metallo-β-lactamases (MBLs).

Purpose of the Study:

• To explore the potential of boronic acids and boronate esters as novel inhibitors of β-lactamases.
• To investigate bicyclic boronates as potent inhibitors for both serine (SBLs) and metallo-β-lactamases (MBLs).

Main Methods:

• Crystallographic analysis to understand enzyme-inhibitor complex formation.
• Exploration of structure-activity relationships for boronate inhibitors.

Main Results:

• Boronic acids and boronate esters, especially cyclic forms, demonstrate potent inhibition of both SBLs and MBLs.
• Bicyclic boronates form stable complexes with SBLs and MBLs, mimicking catalytic intermediates.
• The unique hybridization states of boron contribute to potent inhibition.

Conclusions:

• Boron-based inhibitors, particularly bicyclic boronates, represent a promising strategy to overcome β-lactamase-mediated resistance.
• Further research into structure-activity relationships can lead to the development of new boron-based antibacterials.