Longitudinal evolution of the Pseudomonas-Derived Cephalosporinase (PDC) structure and activity in a cystic fibrosis patient treated with b-Lactams

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dc.citation.titlemBioes
dc.citation.volume13
dc.creatorColque, Claudia A.
dc.creatorAlbarracín Orio, Andrea G.
dc.creatorTomatis, Pablo E.
dc.creatorDotta, Gina
dc.creatorMoreno, Diego M.
dc.creatorHedemann, Laura G.
dc.creatorHickman, Rachel A.
dc.creatorSommer, Lea M.
dc.creatorFeliziani, Sofía
dc.creatorMoyano, Alejandro José
dc.creatorBonomo, Robert A.
dc.creatorJohansen, Helle K.
dc.creatorMolin, Soren
dc.creatorVila, Alejandro J.
dc.creatorSmania, Andrea M.
dc.date.accessioned2023-02-09T17:01:52Z
dc.date.available2023-02-09T17:01:52Z
dc.date.issued2022-09-08
dc.descriptionTraditional 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.es
dc.description.filFil: Colque, Claudia A. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.es
dc.description.filFil: Colque, Claudia A. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.es
dc.description.filFil: Albarracín Orio, Andrea G. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.es
dc.description.filFil: Albarracín Orio, Andrea G. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.es
dc.description.filFil: Albarracín Orio, Andrea G. Universidad Católica de Córdoba. Facultad de Ciencias Agropecuarias. (IRNASUS-CONICET); Argentina.es
dc.description.filFil: Tomatis, Pablo E. Universidad Nacional de Rosario. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.es
dc.description.filFil: Tomatis, Pablo E. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.es
dc.description.filFil: Dotta, Gina. Universidad Nacional de Rosario. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.es
dc.description.filFil: Hedemann, Laura G. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.es
dc.description.filFil: Moreno, Diego M. Universidad Nacional de Rosario. Instituto de Química de Rosario (IQUIR-CONICET); Argentina.es
dc.description.filFil: Moreno, Diego M. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.es
dc.description.filFil: Hedemann, Laura G. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.es
dc.description.filFil: Hickman Rachel A. Technical University of Denmark, Lyngb. Novo Nordisk Foundation Centre for Biosustainability; Denmark.es
dc.description.filFil: Hickman Rachel A. Department of Clinical Microbiology; Denmark.es
dc.description.filFil: Sommer, Lea M. Department of Clinical Microbiology; Denmark.es
dc.description.filFil: Sommer, Lea M. Technical University of Denmark, Lyngb. Novo Nordisk Foundation Centre for Biosustainability; Denmark.es
dc.description.filFil: Feliziani, Sofía. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.es
dc.description.filFil: Feliziani, Sofía. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.es
dc.description.filFil: Moyano, Alejandro José. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.es
dc.description.filFil: Moyano, Alejandro José. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.es
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University. Departments of Molecular Biology and Microbiology, Medicine, Biochemistry, Pharmacology, and Proteomics and Bioinformatics; United States.es
dc.description.filFil: Bonomo, Robert A. Senior Clinical Scientist Investigator. Louis Stokes Cleveland Department of Veterans Affairs; United States.es
dc.description.filFil: Johansen, Helle K. Technical University of Denmark, Lyngb. Novo Nordisk Foundation Centre for Biosustainability; Denmark.es
dc.description.filFil: Johansen, Helle K. Department of Clinical Microbiology; Denmark.es
dc.description.filFil: Johansen, Helle K. University of Copenhagen. Department of Clinical Medicine; Denmark.es
dc.description.filFil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.es
dc.description.filFil: Vila, Alejandro J. Universidad Nacional de Rosario. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.es
dc.description.filFil: Smania, Andrea M. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.es
dc.description.filFil: Smania, Andrea M. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.es
dc.description.sponsorshipCleveland Department of Veterans Affairs: 1I01BX001974
dc.description.sponsorshipMINCyT-Córdoba: PID-2018-Res 144
dc.description.sponsorshipRegionH rammebevilling and Savværksejer Jeppe Juhl og Hustru Ovita Juhls Memorial Fund: R144-A5287
dc.description.sponsorshipNational Institutes of Health: R01AI100560
dc.description.sponsorshipNational Institute of Allergy and Infectious Diseases: R01AI063517
dc.description.sponsorshipMerck
dc.description.sponsorshipBiomedical Laboratory Research and Development, VA Office of Research and Development
dc.description.sponsorshipCase Western Reserve University
dc.description.sponsorshipSecretaria de Ciencia y Tecnología - Universidad Nacional de Córdoba: 33620180100413CB
dc.description.sponsorshipGeriatric Research Education and Clinical Center
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas
dc.description.sponsorshipAgencia Nacional de Promoción Científica y Tecnológica: PICT-2016-1545, PICT-2016-1657, PICT-2016-1926, PICT-2019-1358, PICT-2019-1590
dc.description.sponsorshipDanmarks Frie Forskningsfond: DFF-4183-00051
dc.description.sponsorshipUniversidad de Buenos Aires
dc.description.sponsorshipNovo Nordisk Fonden: NNF12OC1015920, NNF15OC0017444, NNF18OC0052776, R167-2013-15229, R88-A3537
dc.formatapplication/pdf
dc.format.extent1-17es
dc.identifier.issn2161-2129es
dc.identifier.urihttp://hdl.handle.net/2133/25147
dc.language.isoenges
dc.publisherAmerican Society for Microbiologyes
dc.relation.publisherversionhttps://doi.org/10.1128/mbio.01663-22
dc.rightsopenAccesses
dc.rights.holderColque, Claudia A.es
dc.rights.holderAlbarracín Orio, Andrea G.es
dc.rights.holderTomatis, Pablo E.es
dc.rights.holderDotta, Ginaes
dc.rights.holderMoreno, Diego M.es
dc.rights.holderHedemann, Laura G.es
dc.rights.holderHickman, Rachel A.es
dc.rights.holderSommer, Lea M.es
dc.rights.holderFeliziani, Sofíaes
dc.rights.holderMoyano, Alejandro Josées
dc.rights.holderBonomo, Robert A.es
dc.rights.holderJohansen, Helle K.es
dc.rights.holderMolin, Sorenes
dc.rights.holderVila, Alejandro J.es
dc.rights.holderSmania, Andrea M.es
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas
dc.rights.textAttribution 4.0 International (CC BY 4.0)es
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectPseudomonas aeruginosaes
dc.subjectCystic fibrosises
dc.subjectB-lactamase evolutiones
dc.subjectCeftolozane resistancees
dc.subjectHypermutabilityes
dc.titleLongitudinal evolution of the Pseudomonas-Derived Cephalosporinase (PDC) structure and activity in a cystic fibrosis patient treated with b-Lactamses
dc.typearticle
dc.typeartículo
dc.typepublishedVersion
dc.type.collectionarticulo
dc.type.versionpublishedVersiones

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