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Unravelling ceftazidime/avibactam resistance of KPC-28, a KPC-2 variant lacking carbapenemase activity

Saoussen Oueslati1, Bogdan I Iorga2, Linda Tlili1

  • 1EA7361 'Structure, Dynamic, Function and Expression of Broad Spectrum β-Lactamases', Faculty of Medicine, Université Paris-Sud, LabEx Lermit, Université Paris-Saclay, Le Kremlin-Bicêtre, France.

The Journal of Antimicrobial Chemotherapy
|May 26, 2019
PubMed
Abstract

Insights

KPC-28, a carbapenemase variant, shows reduced carbapenemase activity and increased ceftazidime hydrolysis. This variant may be misidentified, necessitating confirmation of carbapenem hydrolysis for accurate diagnostics.

Area of Science:

  • Microbiology
  • Biochemistry
  • Molecular Biology

Background:

  • KPC-like carbapenemases are a global threat with over 30 variants identified.
  • These variants often differ by minor amino acid substitutions.

Purpose of the Study:

  • To characterize the steady-state kinetic parameters of KPC-28.
  • To investigate the impact of specific amino acid changes (H274Y substitution and Δ242-GT-243 deletion) on KPC-28 activity compared to KPC-2.

Main Methods:

  • Cloning of blaKPC genes (blaKPC-2, blaKPC-3, blaKPC-14, blaKPC-28) for expression and purification.
  • Determination of kinetic parameters (Km, kcat) for KPC variants.
  • Molecular docking to explore the role of amino acid alterations.

Main Results:

  • KPC-28 exhibited significantly reduced catalytic efficiency for imipenem hydrolysis (700-fold lower than KPC-2).
  • The H274Y substitution in KPC-28 increased ceftazidime hydrolysis 50-fold, which was reversed by clavulanate.
  • Escherichia coli producing KPC-28 showed lower carbapenem MICs but higher ceftazidime/avibactam MICs compared to KPC-2.

Conclusions:

  • KPC-28 lacks carbapenemase activity and possesses enhanced ceftazidime hydrolytic activity, inhibited by clavulanate.
  • KPC-28-producing E. coli may present an avibactam-resistant ESBL profile, potentially leading to misidentification.
  • Confirmation of carbapenem hydrolysis is crucial for accurate detection, especially when relying solely on blaKPC gene or protein detection.

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