Journal article
Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a Cystic Fibrosis Patient Treated with β-Lactams
Universidad Nacional de Cordoba1
Universidad Nacional de Rosario2
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark3
DTU Microbes Initiative, Centers, Technical University of Denmark4
Data Engineering, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark5
Case Western Reserve University6
Infection Microbiology, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark7
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.
Language: | English |
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Publisher: | American Society for Microbiology |
Year: | 2022 |
Pages: | e0166322 |
ISSN: | 21612129 and 21507511 |
Types: | Journal article |
DOI: | 10.1128/mbio.01663-22 |
ORCIDs: | Hickman, Rachel A. , Sommer, Lea M. , Molin, Søren , 0000-0003-1782-3145 , 0000-0002-4722-1439 , 0000-0002-1126-8200 , 0000-0001-5493-8537 , 0000-0002-4976-7611 , 0000-0002-3299-894X , 0000-0003-0268-3717 , 0000-0002-7978-3233 and 0000-0002-6527-7719 |