Dataset Information

Molecular Evolutionary Analyses of the Pseudomonas-Derived Cephalosporinase Gene.

ABSTRACT: Despite the increasing evidence of the clinical impact of Pseudomonas-derived cephalosporinase (PDC) sequence polymorphisms, the molecular evolution of its encoding gene, bla_PDC, remains elusive. To elucidate this, we performed a comprehensive evolutionary analysis of bla_PDC. A Bayesian Markov Chain Monte Carlo phylogenetic tree revealed that a common ancestor of bla_PDC diverged approximately 4660 years ago, leading to the formation of eight clonal variants (clusters A-H). The phylogenetic distances within clusters A to G were short, whereas those within cluster H were relatively long. Two positive selection sites and many negative selection sites were estimated. Two PDC active sites overlapped with negative selection sites. In docking simulation models based on samples selected from clusters A and H, piperacillin was bound to the serine and the threonine residues of the PDC active sites, with the same binding mode for both models. These results suggest that, in P. aeruginosa, bla_PDC is highly conserved, and PDC exhibits similar antibiotic resistance functionality regardless of its genotype.

SUBMITTER: Shirai T

PROVIDER: S-EPMC10057138 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Molecular Evolutionary Analyses of the Pseudomonas-Derived Cephalosporinase Gene.

Shirai Tatsuya T Akagawa Mao M Makino Miho M Ishii Manami M Arai Ayaka A Nagasawa Norika N Sada Mitsuru M Kimura Ryusuke R Okayama Kaori K Ishioka Taisei T Ishii Haruyuki H Hirai Shinichiro S Ryo Akihide A Tomita Haruyoshi H Kimura Hirokazu H

Microorganisms 20230301 3

Despite the increasing evidence of the clinical impact of Pseudomonas-derived cephalosporinase (PDC) sequence polymorphisms, the molecular evolution of its encoding gene, blaPDC, remains elusive. To elucidate this, we performed a comprehensive evolutionary analysis of blaPDC. A Bayesian Markov Chain Monte Carlo phylogenetic tree revealed that a common ancestor of blaPDC diverged approximately 4660 years ago, leading to the formation of ...[more]

PMID: 36985209

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Project 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.

Dataset Information

Molecular Evolutionary Analyses of the Pseudomonas-Derived Cephalosporinase Gene.

Publications

Molecular Evolutionary Analyses of the <i>Pseudomonas</i>-Derived Cephalosporinase Gene.

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