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Molecular and biochemical insights into the in vivo evolution of AmpC-mediated resistance to ceftolozane/tazobactam during treatment of an MDR Pseudomonas aeruginosa infection.

Author information

Affiliations

  • 1. Servicio de Microbiología-Instituto de Investigación Biomédica (INIBIC), Complexo Hospitalario Universitario A Coruña, A Coruña, Spain.
      Authors
    • Arca-Suárez J 1
    • Vázquez-Ucha JC 1
    • Martínez-Guitián M 1
    • Lasarte-Monterrubio C 1
    • Beceiro A 1
    • Bou G 1
    (6 authors)
  • 2. Servicio de Microbiología and Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria Illes Balears (IdiSBA), Palma de Mallorca, Spain.
      Authors
    • Fraile-Ribot PA 2
    • Cabot G 2
    • Oliver A 2
    (3 authors)
  • 3. Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
      Authors
    • Lence E 3
    • González-Bello C 3
    (2 authors)
  • 4. Servicio de Microbiología and Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar and Departamento de Biomedicina, Biotecnología y Salud Pública, Universidad de Cádiz, Cádiz, Spain.
      Authors
    • Rodríguez-Iglesias M 4
    • Galán-Sánchez F 4
    (2 authors)

ORCIDs linked to this article

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The Journal of Antimicrobial Chemotherapy, 01 Nov 2020, 75(11):3209-3217
https://doi.org/10.1093/jac/dkaa291 PMID: 32728723 

Abstract 

Background

Pseudomonas aeruginosa may develop resistance to novel cephalosporin/β-lactamase inhibitor combinations during therapy through the acquisition of structural mutations in AmpC.

Objectives

To describe the molecular and biochemical mechanisms involved in the development of resistance to ceftolozane/tazobactam in vivo through the selection and overproduction of a novel AmpC variant, designated PDC-315.

Methods

Paired susceptible/resistant isolates obtained before and during ceftolozane/tazobactam treatment were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. Characterization of the novel PDC-315 variant was performed through genotypic and biochemical studies. The effects at the molecular level of the Asp245Asn change were analysed by molecular dynamics simulations using Amber.

Results

WGS identified mutations leading to modification (Asp245Asn) and overproduction of AmpC. Susceptibility testing revealed that PAOΔC producing PDC-315 displayed increased MICs of ceftolozane/tazobactam, decreased MICs of piperacillin/tazobactam and imipenem and similar susceptibility to ceftazidime/avibactam compared with WT PDCs. The catalytic efficiency of PDC-315 for ceftolozane was 10-fold higher in relation to the WT PDCs, but 3.5- and 5-fold lower for piperacillin and imipenem. IC50 values indicated strong inhibition of PDC-315 by avibactam, but resistance to cloxacillin inhibition. Analysis at the atomic level explained that the particular behaviour of PDC-315 is linked to conformational changes in the H10 helix that favour the approximation of key catalytic residues to the active site.

Conclusions

We deciphered the precise mechanisms that led to the in vivo emergence of resistance to ceftolozane/tazobactam in P. aeruginosa through the selection of the novel PDC-315 enzyme. The characterization of this new variant expands our knowledge about AmpC-mediated resistance to cephalosporin/β-lactamase inhibitors in P. aeruginosa.

Full text links 

Read article at publisher's site: https://doi.org/10.1093/jac/dkaa291

Read article for free, from open access legal sources, via Unpaywall: https://academic.oup.com/jac/article-pdf/75/11/3209/33893276/dkaa291.pdfUnpaywall

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Funding 

Funders who supported this work.

Instituto de Salud Carlos III (2)

Ministerio de Economía y Competitividad of Spain