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

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

Claire Amaris Hobson  1 , Stéphane Bonacorsi  1   2 , Hervé Jacquier  1   3 , Alaksh Choudhury  1 , Mélanie Magnan  1 , Aurélie Cointe  1   2 , Béatrice Bercot  1   3 , Olivier Tenaillon  1 , André Birgy  4   2
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KPC Beta-Lactamases Are Permissive to Insertions and Deletions Conferring Substrate Spectrum Modifications and Resistance to Ceftazidime-Avibactam

Claire Amaris Hobson et al. Antimicrob Agents Chemother. .

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.

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Figures

FIG 1
FIG 1
Representation of the protein with the insertion (A) and deletion (B) mutations and the fold increase in MIC to ceftazidime-avibactam (CZA) compared to that of KPC-2.
See this image and copyright information in PMC

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