ArticleAntimicrobial agents and chemotherapy2022
Structural Characterization of the D179N and D179Y Variants of KPC-2 β-Lactamase: Ω-Loop Destabilization as a Mechanism of Resistance to Ceftazidime-Avibactam.
Article in Antimicrobial agents and chemotherapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed, 59 citations in OpenAlex.
- Dynamical-nonequilibrium alanine scanning for identifying allosteric positions in proteins.Biophysical journal · 2026Article
- Reduced catalytic activity of KPC β-lactamase can increase ceftazidime resistance.Communications biology · 2026Article
- Suboptimal ceftazidime-avibactam exposure drives sequentialMicrobiology spectrum · 2026Article
- Article
- Novel Insights into Carbapenem Resistance: Mechanisms, Diagnostics, and Future Directions.Antibiotics (Basel, Switzerland) · 2026Review
- Structural perspectives on clinical β-lactamase inhibitors: From mechanism to resistance.Journal of microbiology (Seoul, Korea) · 2026Review
- Cryptic phenotypic variation emerges rapidly during the adaptive evolution of a carbapenemase.Nature ecology & evolution · 2026Article
- Genomic characterization of ceftazidime/avibactam-resistantFrontiers in microbiology · 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
- Unlocking potentials: the impact of meropenem, meropenem-vaborbactam, and ceftazidime-avibactam in combating carbapenem-resistantAntimicrobial agents and chemotherapy · 2025Article
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Emergence and dissemination ofMicrobiology spectrum · 2025Article
- Rapid replacement of blaKPC variant in ST11 carbapenem-resistant and hypervirulent Klebsiella pneumoniae contributed to ceftazidime/avibactam resistance during severe in vivo infection.The Journal of antimicrobial chemotherapy · 2025Article
- Directed evolution of a beta-lactamase samples a wide variety of conformational states.Protein science : a publication of the Protein Society · 2025Article
- Emerging resistance to novel β-lactam β-lactamase inhibitor combinations in Klebsiella pneumoniae bearing KPC variants.Journal of global antimicrobial resistance · 2025Article
- Article
- Resistance to oxyimino-cephalosporins conferred by an alternative mechanism of hydrolysis by themBio · 2025Article
- Impact of the double deletion ΔG242-T243 in KPC-2 in the effectiveness of ceftazidime-avibactam and imipenem-relebactam.Antimicrobial agents and chemotherapy · 2025Article
- Cefepime-taniborbactam and ceftibuten-ledaborbactam maintain activity against KPC variants that lead to ceftazidime-avibactam resistance.Antimicrobial agents and chemotherapy · 2025Article
- Evolution of ceftazidime-avibactam resistance driven by variation inFrontiers in cellular and infection microbiology · 2025Article
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12 authors at 3 institutions in 1 country.
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Abstract
Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) present a global clinical threat, as these β-lactamases confer resistance to carbapenems and oxyimino-cephalosporins. Recent clinically identified KPC variants with substitutions at Ambler position D179, located in the Ω loop, are resistant to the β-lactam/β-lactamase inhibitor combination ceftazidime-avibactam, but susceptible to meropenem-vaborbactam. To gain insights into ceftazidime-avibactam resistance conferred by D179N/Y variants of KPC-2, crystal structures of these variants were determined. The D179N KPC-2 structure revealed that the change of the carboxyl to an amide moiety at position 179 disrupted the salt bridge with R164 present in wild-type KPC-2. Additional interactions were disrupted in the Ω loop, causing a decrease in the melting temperature. Shifts originating from N179 were also transmitted toward the active site, including ∼1-Å shifts of the deacylation water and interacting residue N170. The structure of the D179Y KPC-2 β-lactamase revealed more drastic changes, as this variant exhibited disorder of the Ω loop, with other flanking regions also being disordered. We postulate that the KPC-2 variants can accommodate ceftazidime because the Ω loop is displaced in D179Y or can be more readily displaced in D179N KPC-2. To understand why the β-lactamase inhibitor vaborbactam is less affected by the D179 variants than avibactam, we determined the crystal structure of D179N KPC-2 in complex with vaborbactam, which revealed wild-type KPC-2-like vaborbactam-active site interactions. Overall, the structural results regarding KPC-2 D179 variants revealed various degrees of destabilization of the Ω loop that contribute to ceftazidime-avibactam resistance, possible substrate-assisted catalysis of ceftazidime, and meropenem and meropenem-vaborbactam susceptibility.
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