KPC Beta-Lactamases Are Permissive to Insertions and Deletions Conferring Substrate Spectrum Modifications and Resistance to Ceftazidime-Avibactam

Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01175-20. doi: 10.1128/AAC.01175-20. Print 2020 Nov 17.

Abstract

To explore the mutational possibilities of insertions and deletions (indels) in the Klebsiella pneumoniae carbapenemase (KPC) beta-lactamase, we selected for ceftazidime-avibactam-resistant mutants. Of 96 screened mutants, we obtained 19 indels (2 to 15 amino acids), all located in the loops surrounding the active site. Three antibiotic susceptibility phenotypes emerged: an extended-spectrum-beta-lactamase-like phenotype, an activity restricted to ceftazidime, and a carbapenem-susceptible KPC-like phenotype. Tolerance for indels reflects the evolvability of KPC beta-lactamase, which could challenge the therapeutic management of patients.

Keywords: KPC; carbapenemase; ceftazidime-avibactam; deletion; hydrolysis spectrum; insertion; mutation; mutational tolerance; omega loop.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Azabicyclo Compounds* / pharmacology
  • Bacterial Proteins / genetics
  • Ceftazidime* / pharmacology
  • Drug Combinations
  • Humans
  • Klebsiella Infections* / drug therapy
  • Klebsiella pneumoniae / genetics
  • Microbial Sensitivity Tests
  • beta-Lactamases / genetics

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Bacterial Proteins
  • Drug Combinations
  • avibactam, ceftazidime drug combination
  • Ceftazidime
  • beta-Lactamases
  • carbapenemase