Boronic Acid Inhibitors of β-Lactamases: A Promising Strategy Against Antimicrobial Resistance.

Abstract

The rise of antimicrobial resistance (AMR) poses a critical threat to global health, mostly due to the proliferation of β-lactamases, a class of enzymes responsible for the inactivation of β-lactam antibiotics. Among the most promising strategies to restore β-lactam efficacy is the use of β-lactamase inhibitors (BLIs), with boronic acid derivatives emerging as a pivotal and chemically versatile class. These compounds act as transition-state analogs, forming reversible covalent bonds with the catalytic serine of serine β-lactamases (SBLs), effectively mimicking the tetrahedral intermediate of β-lactam hydrolysis. Their electron-deficient boron atom, combined with a tunable scaffold, allows fine modulation of potency, selectivity, and pharmacokinetic properties. This review traces the evolution of boronic acid-based BLIs from early phenylboronic acids to next-generation acyclic and cyclic derivatives, highlighting key structure-activity relationships, binding mechanisms, and microbiological profiles. Clinically approved agents such as vaborbactam, as well as investigational compounds including taniborbactam, xeruborbactam, and benzoxaboroles, are discussed in the context of their therapeutic relevance and spectrum of activity. Particular attention is given to their ability to inhibit class A and C enzymes, with ongoing efforts aimed at extending coverage to class D and metallo-β-lactamases. Additionally, the review explores innovative approaches such as kinetic target-guided synthesis and fragment-based design to expand the chemical space of boronic acid pharmacophores. Together, these advances underscore the potential of boronic acid-based BLIs as powerful tools in overcoming β-lactamase-mediated resistance and developing next-generation antimicrobial therapies.