Class D β-Lactamase Mechanisms and Carbapenem Resistance
Summary
Class D β-lactamases, known as oxacillinases, represent a diverse family of serine enzymes that undermine the efficacy of β-lactam antibiotics, notably carbapenems. These enzymes employ a unique carbamylated lysine residue in their active site to facilitate acylation and deacylation of the β-lactam ring. The spectrum of activity ranges from narrow-spectrum penicillinases to potent carbapenemases, with structural variations in active-site loops and surrounding residues mediating substrate selectivity. Carbapenem resistance emerges through enhanced hydrolytic efficiency, structural flexibility that accommodates bulky antibiotics, and synergistic reduction of outer-membrane permeability. Globally, the spread of plasmid-borne OXA variants has precipitated clinical crises, as these enzymes often escape routine detection and compromise last-line therapies. Understanding the interplay between enzyme mechanism, genetic mobility and bacterial physiology is essential to inform surveillance, diagnostic refinement and novel inhibitor design.
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Class D β-Lactamase Mechanisms and Carbapenem Resistance publication trend
The graph below shows the total number of articles in class d β-lactamase mechanisms and carbapenem resistance across all publications each year (not limited to Nature Index journals).
Technical terms
Class D β-Lactamase: A subclass of serine β-lactamases (oxacillinases) that use a carbamylated lysine for catalysis and often hydrolyse carbapenems.
Carbapenem: A class of broad-spectrum β-lactam antibiotics reserved as last-line treatments against multidrug-resistant Gram-negative bacteria.
Acyl-enzyme intermediate: A transient covalent complex formed when the serine residue of the β-lactamase attacks the β-lactam ring during hydrolysis.
Carbamylation: The post-translational modification of a lysine residue by carbon dioxide, essential for the acid–base chemistry in class D β-lactamases.
Outer-membrane permeability: The ability of hydrophilic antibiotics to traverse the bacterial outer membrane, often reduced by porin loss or modification.
Hydrolytic activity: The rate at which β-lactamases cleave the β-lactam ring of antibiotics, determining resistance levels.
References
- An Ion-Pair Induced Intermediate Complex Captured in Class D Carbapenemase Reveals Chloride Ion as a Janus Effector Modulating Activity. ACS Central Science (2023).
- Structural insights into alterations in the substrate spectrum of serine-β-lactamase OXA-10 from Pseudomonas aeruginosa by single amino acid substitutions. Emerging Microbes & Infections (2024).
- Interplay between OXA-10 β-Lactamase Production and Low Outer-Membrane Permeability in Carbapenem Resistance in Enterobacterales. Antibiotics (2023).
- Acquired Class D β-Lactamases. Antibiotics (2014).
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