Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a Cystic Fibrosis Patient Treated with β-Lactams

Colque, Claudia A. ORCID: https://orcid.org/0000-0002-9027-4747, Albarracín Orio, Andrea Georgina ORCID: https://orcid.org/0000-0002-4722-1439, Tomatis, Pablo Emiliano ORCID: https://orcid.org/0000-0002-1126-8200, Dotta, Gina ORCID: https://orcid.org/0000-0003-1023-1606, Moreno, Diego M. ORCID: https://orcid.org/0000-0001-5493-8537, Hedemann, Laura Gabriela ORCID: https://orcid.org/0000-0002-6667-6500, Hickman, Rachel ORCID: https://orcid.org/0000-0002-0290-1836, Madsen Sommer, Lea Mette ORCID: https://orcid.org/0000-0002-1622-6691, Feliziani, Sofía, Moyano, Alejandro José ORCID: https://orcid.org/0000-0002-4976-7611, Bonomo, Robert ORCID: https://orcid.org/0000-0002-3299-894X, Johansen, Helle Krogh ORCID: https://orcid.org/0000-0003-0268-3717, Molin, Søren ORCID: https://orcid.org/0000-0002-7973-2639, Vila, Alejandro ORCID: https://orcid.org/0000-0002-7978-3233 and Smania, Andrea M. (2022) Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a Cystic Fibrosis Patient Treated with β-Lactams. mBio, 13 (5).

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Resumen

Traditional studies on the evolution of antibiotic resistance development use approaches that can range from laboratory-based experimental studies, to epidemiological surveillance, to sequencing of clinical isolates. However, evolutionary trajectories also depend on the environment in which selection takes place, compelling the need to more deeply investigate the impact of environmental complexities and their dynamics over time. Herein, we explored the within-patient adaptive long-term evolution of a Pseudomonas aeruginosa hypermutator lineage in the airways of a cystic fibrosis (CF) patient by performing a chronological tracking of mutations that occurred in different subpopulations; our results demonstrated parallel evolution events in the chromosomally encoded class C b-lactamase (blaPDC). These multiple mutations within blaPDC shaped diverse coexisting alleles, whose frequency dynamics responded to the changing antibiotic selective pressures for more than 26 years of chronic infection. Importantly, the combination of the cumulative mutations in blaPDC provided structural and functional protein changes that resulted in a continuous enhancement of its catalytic efficiency and high level of cephalosporin resistance. This evolution was linked to the persistent treatment with ceftazidime, which we demonstrated selected for variants with robust catalytic activity against this expanded-spectrum cephalosporin. A “gain of function” of collateral resistance toward ceftolozane, a more recently introduced cephalosporin that was not prescribed to this patient, was also observed, and the biochemical basis of this cross-resistance phenomenon was elucidated. This work unveils the evolutionary trajectories paved by bacteria toward a multidrug-resistant phenotype, driven by decades of antibiotic treatment in the natural CF environmental setting.

Tipo de documento:	Artículo
DOI:	0.1128/mbio.01663-22
Palabras clave:	Pseudomonas aeruginosa. Cystic fibrosis. b-lactamase evolution. Ceftolozane resistance. Hypermutability.
Temas:	R Medicina > R Medicina (General)
Unidad académica:	Universidad Católica de Córdoba > Facultad de Ciencias Agropecuarias Universidad Católica de Córdoba > Facultad de Ciencias Químicas
Google Académico:	Ver citaciones
URI:	http://pa.bibdigital.ucc.edu.ar/id/eprint/3687

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