Metallo-β-Lactamase Biochemistry and Antibiotic Resistance

Metallo-β-lactamases (MBLs) pose a global threat by inactivating β-lactam antibiotics, including penicillins, cephalosporins and carbapenems. These enzymes employ one or two zinc ions at their active site to catalyse the hydrolytic opening of the β-lactam ring, rendering antibiotics ineffective. The structural diversity of MBLs, categorised into subclasses B1, B2 and B3, underlies variations in substrate specificity, metal dependence and inhibitor susceptibility. Advances in mechanistic studies have elucidated a unified reaction pathway for mono- and binuclear MBLs, revealing conserved anionic intermediates and facilitating rational inhibitor design. The rapid evolution of variants, particularly New Delhi MBL (NDM) enzymes, has resulted in enhanced stability, altered zinc affinity and mono-zinc activity, further complicating therapeutic challenges. Understanding loop dynamics, gating interactions and metal-ion coordination has illuminated potential targets for novel inhibitors. Beyond clinical resistance, MBL fold proteins are widespread among bacteria, archaea and eukaryotes, exhibiting multifarious roles from nucleic acid processing to detoxification. Addressing MBL-mediated resistance demands integrated efforts in biochemistry, structural biology and drug discovery to safeguard last-resort antibiotics.

Research from Nature Portfolio

Studies on the chemical mechanism of carbapenem hydrolysis have delineated a stepwise pathway shared by mono- and binuclear MBLs, identifying key anionic intermediates and elucidating metal-ligand interactions that stabilise transition states. Comparative structural analysis of MBLs complexed with hydrolysed carbapenems has revealed distinct tautomerisation events and protonation patterns unique to NDM-1, suggesting novel approaches for mechanism-based inhibitor design. Investigations into MBL dissemination have uncovered that signal peptide composition and processing efficiency dictate the fitness cost of MBL expression in different bacterial hosts, explaining the differential spread of VIM, SPM and NDM variants and highlighting factors underpinning global resistance patterns.

Metallo-β-Lactamase Biochemistry and Antibiotic Resistance publication trend

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

Technical terms

Metallo-β-lactamases (MBLs): Enzymes that hydrolyse β-lactam antibiotics using zinc ion cofactors.

Carbapenems: A class of β-lactam antibiotics often reserved as a last-resort treatment.

Active site: The region of an enzyme where substrate binding and catalysis occur.

Hydrolysis: Chemical cleavage of a bond through the addition of water.

Mono- and binuclear centres: Enzyme active sites containing one or two zinc ions, respectively.

Intermediate: A transient chemical species formed during the catalytic reaction pathway.

Inhibitor: A molecule that binds to an enzyme to decrease its catalytic activity.

References

1. A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases. Nature Communications (2017).
2. Evolution of New Delhi metallo-β-lactamase (NDM) in the clinic: Effects of NDM mutations on stability, zinc affinity, and mono-zinc activity. Journal of Biological Chemistry (2018).
3. Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase. eLife (2023).
4. Auranofin Targeting the NDM-1 Beta-Lactamase: Computational Insights into the Electronic Configuration and Quasi-Tetrahedral Coordination of Gold Ions. Pharmaceutics (2023).
5. Origin, Diversity, and Multiple Roles of Enzymes with Metallo-β-Lactamase Fold from Different Organisms. Cells (2023).
6. Identification of 76 novel B1 metallo-β-lactamases through large-scale screening of genomic and metagenomic data. Microbiome (2017).
7. The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis. Nature Communications (2017).
8. Protein determinants of dissemination and host specificity of metallo-β-lactamases. Nature Communications (2019).