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

Claire Amaris Hobson; Stéphane Bonacorsi; Hervé Jacquier; Alaksh Choudhury; Mélanie Magnan; Aurélie Cointe; Béatrice Bercot; Olivier Tenaillon; André Birgy

doi:10.1128/AAC.01175-20

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

Claire Amaris Hobson, Stéphane Bonacorsi, Hervé Jacquier, Alaksh Choudhury, Mélanie Magnan, Aurélie Cointe, Béatrice Bercot, Olivier Tenaillon, André Birgy

Research output: Contribution to journal › Article › peer-review

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-betalactamase-like phenotype, an activity restricted to ceftazidime, and a carbapenemsusceptible KPC-like phenotype. Tolerance for indels reflects the evolvability of KPC beta-lactamase, which could challenge the therapeutic management of patients.

Original language	English
Article number	e01175-20
Journal	Antimicrobial Agents and Chemotherapy
Volume	64
Issue number	12
DOIs	https://doi.org/10.1128/AAC.01175-20
Publication status	Published - 1 Dec 2020
Externally published	Yes

Keywords

Carbapenemase
Ceftazidime-avibactam
Deletion
Hydrolysis spectrum
Insertion
KPC
Mutation
Mutational tolerance
Omega loop

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hobson, C. A., Bonacorsi, S., Jacquier, H., Choudhury, A., Magnan, M., Cointe, A., Bercot, B., Tenaillon, O., & Birgy, A. (2020). KPC Beta-Lactamases Are Permissive to Insertions and Deletions Conferring Substrate Spectrum Modifications and Resistance to Ceftazidime-Avibactam. Antimicrobial Agents and Chemotherapy, 64(12), Article e01175-20. https://doi.org/10.1128/AAC.01175-20

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

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-betalactamase-like phenotype, an activity restricted to ceftazidime, and a carbapenemsusceptible KPC-like phenotype. Tolerance for indels reflects the evolvability of KPC beta-lactamase, which could challenge the therapeutic management of patients.",

keywords = "Carbapenemase, Ceftazidime-avibactam, Deletion, Hydrolysis spectrum, Insertion, KPC, Mutation, Mutational tolerance, Omega loop",

author = "Hobson, \{Claire Amaris\} and St{\'e}phane Bonacorsi and Herv{\'e} Jacquier and Alaksh Choudhury and M{\'e}lanie Magnan and Aur{\'e}lie Cointe and B{\'e}atrice Bercot and Olivier Tenaillon and Andr{\'e} Birgy",

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doi = "10.1128/AAC.01175-20",

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T1 - KPC Beta-Lactamases Are Permissive to Insertions and Deletions Conferring Substrate Spectrum Modifications and Resistance to Ceftazidime-Avibactam

AU - Hobson, Claire Amaris

AU - Bonacorsi, Stéphane

AU - Jacquier, Hervé

AU - Choudhury, Alaksh

AU - Magnan, Mélanie

AU - Cointe, Aurélie

AU - Bercot, Béatrice

AU - Tenaillon, Olivier

AU - Birgy, André

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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-betalactamase-like phenotype, an activity restricted to ceftazidime, and a carbapenemsusceptible KPC-like phenotype. Tolerance for indels reflects the evolvability of KPC beta-lactamase, which could challenge the therapeutic management of patients.

AB - 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-betalactamase-like phenotype, an activity restricted to ceftazidime, and a carbapenemsusceptible KPC-like phenotype. Tolerance for indels reflects the evolvability of KPC beta-lactamase, which could challenge the therapeutic management of patients.

KW - Carbapenemase

KW - Ceftazidime-avibactam

KW - Deletion

KW - Hydrolysis spectrum

KW - Insertion

KW - KPC

KW - Mutation

KW - Mutational tolerance

KW - Omega loop

U2 - 10.1128/AAC.01175-20

DO - 10.1128/AAC.01175-20

M3 - Article

C2 - 33020157

AN - SCOPUS:85096363472

SN - 0066-4804

VL - 64

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 12

M1 - e01175-20

ER -

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

Abstract

Keywords

UN SDGs

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