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

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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 selectio...

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Autores principales: Colque, Claudia A., Albarracín Orio, Andrea G., Tomatis, Pablo E., Dotta, Gina, Moreno, Diego M., Hedemann, Laura G., Hickman, Rachel A., Sommer, Lea M., Feliziani, Sofía, Moyano, Alejandro J., Bonomo, Robert A., Johansen, Helle K., Molin, Soren, Vila, Alejandro J., Smania, Andrea M.
Formato: article artículo publishedVersion
Lenguaje:Inglés
Publicado: American Society for Microbiology 2023
Materias:
Pseudomonas aeruginosa
Cystic fibrosis
B-lactamase evolution
Ceftolozane resistance
Hypermutability
Acceso en línea:http://hdl.handle.net/2133/25147
http://hdl.handle.net/2133/25147
Aporte de:
Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR) de Universidad Nacional de Rosario
id I15-R121-2133-25147
record_format dspace
institution Universidad Nacional de Rosario
institution_str I-15
repository_str R-121
collection Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR)
language Inglés
topic Pseudomonas aeruginosa
Cystic fibrosis
B-lactamase evolution
Ceftolozane resistance
Hypermutability
spellingShingle Pseudomonas aeruginosa
Cystic fibrosis
B-lactamase evolution
Ceftolozane resistance
Hypermutability
Colque, Claudia A.
Albarracín Orio, Andrea G.
Tomatis, Pablo E.
Dotta, Gina
Moreno, Diego M.
Hedemann, Laura G.
Hickman, Rachel A.
Sommer, Lea M.
Feliziani, Sofía
Moyano, Alejandro J.
Bonomo, Robert A.
Johansen, Helle K.
Molin, Soren
Vila, Alejandro J.
Smania, Andrea M.
Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a CysticFibrosis Patient Treated with b-Lactams
topic_facet Pseudomonas aeruginosa
Cystic fibrosis
B-lactamase evolution
Ceftolozane resistance
Hypermutability
description 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 β-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. IMPORTANCE Antibiotics are becoming increasingly ineffective to treat bacterial infections. It has been consequently predicted that infectious diseases will become the biggest challenge to human health in the near future. Pseudomonas aeruginosa is considered a paradigm in antimicrobial resistance as it exploits intrinsic and acquired resistance mechanisms to resist virtually all antibiotics known. AmpC β-lactamase is the main mechanism driving resistance in this notorious pathogen to β-lactams, one of the most widely used classes of antibiotics for cystic fibrosis infections. Here, we focus on the β-lactamase gene as a model resistance determinant and unveil the trajectory P. aeruginosa undertakes on the path toward a multidrug-resistant phenotype during the course of two and a half decades of chronic infection in the airways of a cystic fibrosis patient. Integrating genetic and biochemical studies in the natural environment where evolution occurs, we provide a unique perspective on this challenging landscape, addressing fundamental molecular mechanisms of resistance.
format article
artículo
publishedVersion
author Colque, Claudia A.
Albarracín Orio, Andrea G.
Tomatis, Pablo E.
Dotta, Gina
Moreno, Diego M.
Hedemann, Laura G.
Hickman, Rachel A.
Sommer, Lea M.
Feliziani, Sofía
Moyano, Alejandro J.
Bonomo, Robert A.
Johansen, Helle K.
Molin, Soren
Vila, Alejandro J.
Smania, Andrea M.
author_facet Colque, Claudia A.
Albarracín Orio, Andrea G.
Tomatis, Pablo E.
Dotta, Gina
Moreno, Diego M.
Hedemann, Laura G.
Hickman, Rachel A.
Sommer, Lea M.
Feliziani, Sofía
Moyano, Alejandro J.
Bonomo, Robert A.
Johansen, Helle K.
Molin, Soren
Vila, Alejandro J.
Smania, Andrea M.
author_sort Colque, Claudia A.
title Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a CysticFibrosis Patient Treated with b-Lactams
title_short Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a CysticFibrosis Patient Treated with b-Lactams
title_full Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a CysticFibrosis Patient Treated with b-Lactams
title_fullStr Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a CysticFibrosis Patient Treated with b-Lactams
title_full_unstemmed Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a CysticFibrosis Patient Treated with b-Lactams
title_sort longitudinal evolution of the pseudomonas-derived cephalosporinase (pdc) structure and activity in a cysticfibrosis patient treated with b-lactams
publisher American Society for Microbiology
publishDate 2023
url http://hdl.handle.net/2133/25147
http://hdl.handle.net/2133/25147
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