ArticleThe Journal of biological chemistry
KPC-2 β-lactamase enables carbapenem antibiotic resistance through fast deacylation of the covalent intermediate.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 37 citations in OpenAlex.
- Dynamical-nonequilibrium alanine scanning for identifying allosteric positions in proteins.Biophysical journal · 2026Article
- The Novel Carbapenem, JDB/PQ-1-219, Has Potent Broad Spectrum Activity against Multi-Drug ResistantACS infectious diseases · 2026Article
- Genetic diversity and occurrence of antibiotic resistance genes from community wastewater in Dhaka and Cox's Bazar, Bangladesh.One health (Amsterdam, Netherlands) · 2026Article
- Data-driven design and screening of novelRSC advances · 2026Article
- Reduced catalytic activity of KPC β-lactamase can increase ceftazidime resistance.Communications biology · 2026Article
- Phosphate sensitivity of KPC-2: a hidden variable in β-lactamase kinetics.Antimicrobial agents and chemotherapy · 2026Article
- Structural perspectives on clinical β-lactamase inhibitors: From mechanism to resistance.Journal of microbiology (Seoul, Korea) · 2026Review
- Genomic Epidemiology and Antimicrobial Resistance Analyses ofInfection and drug resistance · 2026Article
- Structural insights into the activity of carbapenemases: understanding the mechanism of action of current inhibitors and informing the design of new carbapenem adjuvants.RSC medicinal chemistry · 2025Review
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- The mechanisms of antibiotic resistance and drug resistance transmission of Klebsiella pneumoniae.The Journal of antibiotics · 2025Review
- Dual mechanism of the OXA-23 carbapenemase inhibition by the carbapenem NA-1-157.Antimicrobial agents and chemotherapy · 2025Article
- Catalytic Residue Reprogramming Enhances Enzyme Activity at Alkaline pH via Phenolate-Mediated Proton Transfer.ACS synthetic biology · 2025Article
- Article
- Prevalence of on time administration of carbapenem and its impact on PK/PD target attainment in hospitalized patients: a multicenter retrospective study.Frontiers in cellular and infection microbiology · 2025Article
- Characterization of GQA as a novel β-lactamase inhibitor of CTX-M-15 and KPC-2 enzymes.Microbial cell factories · 2024Article
- Detection of hidden antibiotic resistance through real-time genomics.Nature communications · 2024Article
- Electric Fields Are a Key Determinant of Carbapenemase Activity in Class A β-Lactamases.ACS catalysis · 2024Article
- The mechanism of ceftazidime and cefiderocol hydrolysis by D179Y variants of KPC carbapenemases is similar and involves the formation of a long-lived covalent intermediate.Antimicrobial agents and chemotherapy · 2024Article
- Structural role of K224 in taniborbactam inhibition of NDM-1.Antimicrobial agents and chemotherapy · 2024Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Serine active-site β-lactamases hydrolyze β-lactam antibiotics through the formation of a covalent acyl-enzyme intermediate followed by deacylation via an activated water molecule. Carbapenem antibiotics are poorly hydrolyzed by most β-lactamases owing to slow hydrolysis of the acyl-enzyme intermediate. However, the emergence of the KPC-2 carbapenemase has resulted in widespread resistance to these drugs, suggesting it operates more efficiently. Here, we investigated the unusual features of KPC-2 that enable this resistance. We show that KPC-2 has a 20,000-fold increased deacylation rate compared with the common TEM-1 β-lactamase. Furthermore, kinetic analysis of active site alanine mutants indicates that carbapenem hydrolysis is a concerted effort involving multiple residues. Substitution of Asn170 greatly decreases the deacylation rate, but this residue is conserved in both KPC-2 and non-carbapenemase β-lactamases, suggesting it promotes carbapenem hydrolysis only in the context of KPC-2. X-ray structure determination of the N170A enzyme in complex with hydrolyzed imipenem suggests Asn170 may prevent the inactivation of the deacylating water by the 6α-hydroxyethyl substituent of carbapenems. In addition, the Thr235 residue, which interacts with the C3 carboxylate of carbapenems, also contributes strongly to the deacylation reaction. In contrast, mutation of the Arg220 and Thr237 residues decreases the acylation rate and, paradoxically, improves binding affinity for carbapenems. Thus, the role of these residues may be ground state destabilization of the enzyme-substrate complex or, alternatively, to ensure proper alignment of the substrate with key catalytic residues to facilitate acylation. These findings suggest modifications of the carbapenem scaffold to avoid hydrolysis by KPC-2 β-lactamase.
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