Antimicrobial Resistance and Metallo-β-Lactamase Inhibition

Antimicrobial resistance poses a growing global threat, particularly through the emergence of Gram-negative bacteria that produce metallo-β-lactamases (MBLs). These zinc-dependent enzymes hydrolyse a broad range of β-lactam antibiotics, including last-resort carbapenems, rendering many treatments ineffective. Inhibiting MBLs is challenging due to their reliance on metal cofactors and structural diversity, yet it remains a priority for restoring antibiotic efficacy. Recent advances have focused on agents capable of displacing zinc ions from the active site, mimicking transition-state intermediates to block catalysis, or combining antibacterial delivery systems with metal chelation strategies. Efforts span from small-molecule inhibitors that target both MBLs and serine-β-lactamases to repurposed metallodrugs that act synergistically with existing antibiotics. Such approaches aim not only to curb acute infections but also to limit the evolution of further resistance by slowing enzyme adaptation. Integrating structural insights with innovative drug delivery and metabolic modulation holds promise for developing broadly effective MBL inhibitors and reviving the utility of frontline β-lactam therapies.

Research from Nature Portfolio

Studies have demonstrated that cyclic boronate scaffolds can function as dual inhibitors of serine- and metallo-β-lactamases by mimicking the tetrahedral intermediate of β-lactam hydrolysis. Structural analyses reveal precise binding modes that inform the optimisation of broad-spectrum inhibitors with activity against multiple enzyme classes and potential additional targeting of penicillin-binding proteins.

Work on bismuth compounds has shown that Bi(III) agents irreversibly displace zinc cofactors in diverse MBLs, restoring the potency of carbapenem antibiotics in vitro and in animal infection models, while also mitigating the evolution of higher-level resistance over successive bacterial generations.

A recent report identified an antirheumatic gold compound capable of simultaneously inhibiting MBLs and mobilised colistin resistance proteins by zinc displacement. This dual-action profile synergises with carbapenem and colistin regimens to eradicate multidrug-resistant strains in preclinical infection models and delay the emergence of resistance.

Antimicrobial Resistance and Metallo-β-Lactamase Inhibition publication trend

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

Technical terms

Antimicrobial resistance: The capacity of microorganisms to survive exposure to agents that once eradicated them.

Metallo-β-lactamase (MBL): A zinc-dependent enzyme that hydrolyses β-lactam antibiotics, conferring drug resistance.

Serine-β-lactamase (SBL): A β-lactamase that uses an active-site serine residue to cleave the β-lactam ring.

Carbapenem: A class of broad-spectrum β-lactam antibiotics often reserved for multidrug-resistant infections.

Zn(II) cofactor: A divalent zinc ion essential for metallo-β-lactamase catalytic activity.

Broad-spectrum inhibitor: A compound capable of suppressing multiple β-lactamase classes.

References

1. Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates. Nature Communications (2016).
2. Bismuth antimicrobial drugs serve as broad-spectrum metallo-β-lactamase inhibitors. Nature Communications (2018).
3. Resensitizing carbapenem- and colistin-resistant bacteria to antibiotics using auranofin. Nature Communications (2020).
4. Liposomal Antibiotic Booster Potentiates Carbapenems for Combating NDMs‐Producing Escherichia coli. Advanced Science (2023).
5. Oxidized glutathione reverts carbapenem resistance in blaNDM-1-carrying Escherichia coli. EMBO Molecular Medicine (2024).
6. Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections. Journal of Medicinal Chemistry (2019).