ArticleAntimicrobial agents and chemotherapy2012
Crystal structures of KPC-2 β-lactamase in complex with 3-nitrophenyl boronic acid and the penam sulfone PSR-3-226.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 50 citations in OpenAlex.
- 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
- Identification of two KPC variants, KPC-204 and KPC-227, in ST11-K64Frontiers in microbiology · 2025Article
- Trends on Potential Boron-containing Drugs by Advancements in Ligand-protein Crystals Complexes.Current medicinal chemistry · 2025Review
- Restricted Rotational Flexibility of the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase.ACS infectious diseases · 2024Article
- Aromatic Diboronic Acids as Effective KPC/AmpC Inhibitors.Molecules (Basel, Switzerland) · 2023Article
- Boronic Acid Transition State Inhibitors as Potent Inactivators of KPC and CTX-M β-Lactamases: Biochemical and Structural Analyses.Antimicrobial agents and chemotherapy · 2023Article
- Structural Characterization of the D179N and D179Y Variants of KPC-2 β-Lactamase: Ω-Loop Destabilization as a Mechanism of Resistance to Ceftazidime-Avibactam.Antimicrobial agents and chemotherapy · 2022Article
- Structural basis to repurpose boron-based proteasome inhibitors Bortezomib and Ixazomib as β-lactamase inhibitors.Scientific reports · 2022Article
- Metallacarborane Derivatives Effective againstInternational journal of molecular sciences · 2021Article
- Allosteric communication in class A β-lactamases occurs via cooperative coupling of loop dynamics.eLife · 2021Article
- Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations.Frontiers in molecular biosciences · 2021Article
- Structural Comparisons of Cefotaximase (CTX-M-ase) Sub Family 1.Frontiers in microbiology · 2021Review
- Influence of substrates and inhibitors on the structure ofExperimental biology and medicine (Maywood, N.J.) · 2019Review
- Defining the architecture of KPC-2 Carbapenemase: identifying allosteric networks to fight antibiotics resistance.Scientific reports · 2018Article
- Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using β-Lactamase Inhibitors and β-Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234.Journal of medicinal chemistry · 2018Article
- In silico identification and experimental validation of hits active against KPC-2 β-lactamase.PloS one · 2018Article
- Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches.Frontiers in microbiology · 2018Review
- Search for non-lactam inhibitors of mtb β-lactamase led to its open shape in apo state: new concept for antibiotic design.Scientific reports · 2017Article
- Carbapenem-Resistant Enterobacteriaceae.Clinics in laboratory medicine · 2017Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Class A carbapenemases are a major threat to the potency of carbapenem antibiotics. A widespread carbapenemase, KPC-2, is not easily inhibited by β-lactamase inhibitors (i.e., clavulanic acid, sulbactam, and tazobactam). To explore different mechanisms of inhibition of KPC-2, we determined the crystal structures of KPC-2 with two β-lactamase inhibitors that follow different inactivation pathways and kinetics. The first complex is that of a small boronic acid compound, 3-nitrophenyl boronic acid (3-NPBA), bound to KPC-2 with 1.62-Å resolution. 3-NPBA demonstrated a K(m) value of 1.0 ± 0.1 μM (mean ± standard error) for KPC-2 and blocks the active site by making a reversible covalent interaction with the catalytic S70 residue. The two boron hydroxyl atoms of 3-NPBA are positioned in the oxyanion hole and the deacylation water pocket, respectively. In addition, the aromatic ring of 3-NPBA provides an edge-to-face interaction with W105 in the active site. The structure of KPC-2 with the penam sulfone PSR-3-226 was determined at 1.26-Å resolution. PSR-3-226 displayed a K(m) value of 3.8 ± 0.4 μM for KPC-2, and the inactivation rate constant (k(inact)) was 0.034 ± 0.003 s(-1). When covalently bound to S70, PSR-3-226 forms a trans-enamine intermediate in the KPC-2 active site. The predominant active site interactions are generated via the carbonyl oxygen, which resides in the oxyanion hole, and the carboxyl moiety of PSR-3-226, which interacts with N132, N170, and E166. 3-NPBA and PSR-3-226 are the first β-lactamase inhibitors to be trapped as an acyl-enzyme complex with KPC-2. The structural and inhibitory insights gained here could aid in the design of potent KPC-2 inhibitors.
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