β-Lactamase Inhibition Strategies in Antibiotic Resistance Management

β-Lactam antibiotics have underpinned modern antibacterial therapy for decades, yet their efficacy is increasingly compromised by the widespread production of β-lactamases, enzymes that hydrolyse the characteristic β-lactam ring. Inhibiting these enzymes is crucial to restoring antibiotic potency. Early inhibitors such as clavulanic acid, sulbactam and tazobactam act as mechanism-based “suicide” substrates against serine β-lactamases (SBLs), but offer little activity against metallo-β-lactamases (MBLs). The advent of non-β-lactam diazabicyclooctane inhibitors, exemplified by avibactam, has expanded the spectrum to classes A, C and some D SBLs through reversible covalent acylation. More recently, boronic acid derivatives and cyclic boronates have emerged as powerful transition-state mimics capable of inhibiting both SBLs and MBLs in vitro, signalling progress towards dual-action inhibitors. Structure-guided design and high-throughput screening, coupled with computational repurposing of existing drugs, are rapidly diversifying the inhibitor arsenal. Combination therapies pairing improved inhibitors with legacy β-lactams are being optimised to overcome diverse resistance mechanisms, with global implications for managing multidrug-resistant Gram-negative infections.

Research from Nature Portfolio

No recent Nature Portfolio content available.

β-Lactamase Inhibition Strategies in Antibiotic Resistance Management publication trend

The graph below shows the total number of articles in β-lactamase inhibition strategies in antibiotic resistance management across all publications each year (not limited to Nature Index journals).

Technical terms

β-Lactamase: bacterial enzyme that hydrolyses the β-lactam ring of antibiotics, rendering them inactive.

β-Lactamase inhibitor (BLI): compound that prevents β-lactamase from cleaving β-lactam antibiotics.

Serine β-lactamases (SBLs): class of β-lactamases using an active-site serine residue to hydrolyse β-lactams.

Metallo-β-lactamases (MBLs): zinc-dependent enzymes that inactivate β-lactams via metal-mediated hydrolysis.

Transition state inhibitor: molecule that mimics an enzyme’s high-energy intermediate, binding tightly to block catalysis.

References

1. Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits Acinetobacter-Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum. Journal of Medicinal Chemistry (2023).
2. Structure-guided drug repurposing identifies aristospan as a potential inhibitor of β-lactamase: insights from virtual screening and molecular dynamics simulations. Frontiers in Pharmacology (2024).
3. Role of β-Lactamase Inhibitors as Potentiators in Antimicrobial Chemotherapy Targeting Gram-Negative Bacteria. Antibiotics (2024).
4. Cyclic Boronates Inhibit All Classes of β-Lactamases. Antimicrobial Agents and Chemotherapy (2017).
5. Kinetics of Avibactam Inhibition against Class A, C, and D β-Lactamases. Journal of Biological Chemistry (2013).