ArticleAntimicrobial agents and chemotherapy2010
Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor.
Article in Antimicrobial agents and chemotherapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers, 2 of them syntheses that pooled it.
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Who cites it
73 citing papers in PubMed, 2 syntheses or guidelines pooled it, 140 citations in OpenAlex.
- Pharmacological aspects and spectrum of action of ceftazidime-avibactam: a systematic review.Infection · 2018Pooled it
- Structural basis for carbapenem-hydrolyzing mechanisms of carbapenemases conferring antibiotic resistance.International journal of molecular sciences · 2015Pooled it
- Trial
- Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2016Trial
- Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studies.Clinical drug investigation · 2015Trial
- Single- and multiple-dose study to determine the safety, tolerability, and pharmacokinetics of ceftaroline fosamil in combination with avibactam in healthy subjects.Antimicrobial agents and chemotherapy · 2013Trial
- Engineering fusion enzymes for enhanced catalysis and stability: strategies and biotechnological applications.Molecular biology reports · 2026Review
- Review
- Genomic characterization of ceftazidime/avibactam-resistantFrontiers in microbiology · 2026Article
- Avibactam-Cyclodextrin Inclusion Complexes: Computational and Thermodynamic Insights for Drug Delivery, Detection, and Environmental Scavenging.Molecules (Basel, Switzerland) · 2025Article
- The Role ofInfection and drug resistance · 2025Article
- Revitalizing cephalosporins: The promise of β-lactamase inhibitor combinations.GMS hygiene and infection control · 2025Article
- Revisiting the Metallo-International journal of microbiology · 2025Review
- Antimicrobial resistance inScience in One Health · 2025Review
- Metabolomics unveil key pathways underlying the synergistic activities of aztreonam and avibactam against multidrug-resistant Escherichia coli.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2024Article
- Meropenem-ANT3310, a unique β-lactam-β-lactamase inhibitor combination with expanded antibacterial spectrum against Gram-negative pathogens including carbapenem-resistantAntimicrobial agents and chemotherapy · 2024Article
- Variability of bile bacterial profiles and drug resistance in patients with choledocholithiasis combined with biliary tract infection: a retrospective study.Gastroenterology report · 2024Article
- Pharmacokinetic/Pharmacodynamic Evaluation of Aztreonam/Amoxicillin/Clavulanate Combination against New Delhi Metallo-β-Lactamase and Serine-β-Lactamase Co-ProducingPharmaceutics · 2023Article
- Protein Electric Fields Enable Faster and Longer-Lasting Covalent Inhibition of β-Lactamases.Journal of the American Chemical Society · 2022Article
- Broad-Spectrum Inhibitors against Class A, B, and C Type β-Lactamases to Block the Hydrolysis against Antibiotics: Kinetics and Structural Characterization.Microbiology spectrum · 2022Article
13 more citing papers are in PubMed but not listed here.
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8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
NXL104 is a potent inhibitor of class A and C serine β-lactamases, including KPC carbapenemases. Native and NXL104-inhibited TEM-1 and P99 β-lactamases analyzed by liquid chromatography-electrospray ionization-time of flight mass spectrometry revealed that the inactivated enzymes formed a covalent adduct with NXL104. The principal inhibitory characteristics of NXL104 against TEM-1 and P99 β-lactamases were determined, including partition ratios, dissociation constants (K), rate constants for deactivation (k(2)), and reactivation rates. NXL104 is a potent inhibitor of TEM-1 and P99, characterized by high carbamylation efficiencies (k(2)/K of 3.7 × 10(5) M(-1) s(-1) for TEM-1 and 1 × 10(4) M(-1) s(-1) for P99) and slow decarbamylation. Complete loss of β-lactamase activity was obtained at a 1/1 enzyme/NXL104 ratio, with a k(3) value (rate constant for formation of product and free enzyme) close to zero for TEM-1 and P99. Fifty percent inhibitory concentrations (IC(50)s) were evaluated on selected β-lactamases, and NXL104 was shown to be a very potent inhibitor of class A and C β-lactamases. IC(50)s obtained with NXL104 (from 3 nM to 170 nM) were globally comparable on the β-lactamases CTX-M-15 and SHV-4 with those obtained with the comparators (clavulanate, tazobactam, and sulbactam) but were far lower on TEM-1, KPC-2, P99, and AmpC than those of the comparators. In-depth studies on TEM-1 and P99 demonstrated that NXL104 had a comparable or better affinity and inactivation rate than clavulanate and tazobactam and in all cases an improved stability of the covalent enzyme/inhibitor complex.
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