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Integrated Experimental and Computational Analyses Reveal Differential Metabolic Functionality in Antibiotic-Resistant Pseudomonas aeruginosa.

ABSTRACT: Metabolic adaptations accompanying the development of antibiotic resistance in bacteria remain poorly understood. To study this relationship, we profiled the growth of lab-evolved antibiotic-resistant lineages of the opportunistic pathogen Pseudomonas aeruginosa across 190 unique carbon sources. Our data revealed that the evolution of antibiotic resistance resulted in systems-level changes to growth dynamics and metabolic phenotype. A genome-scale metabolic network reconstruction of P. aeruginosa was paired with whole-genome sequencing data to predict genes contributing to observed changes in metabolism. We experimentally validated computational predictions to identify mutations in resistant P. aeruginosa affecting loss of catabolic function. Finally, we found a shared metabolic phenotype between lab-evolved P. aeruginosa and clinical isolates with similar mutational landscapes. Our results build upon previous knowledge of antibiotic-induced metabolic adaptation and provide a framework for the identification of metabolic limitations in antibiotic-resistant pathogens.

SUBMITTER: Dunphy LJ

PROVIDER: S-EPMC6345604 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Integrated Experimental and Computational Analyses Reveal Differential Metabolic Functionality in Antibiotic-Resistant Pseudomonas aeruginosa.

Dunphy Laura J LJ Yen Phillip P Papin Jason A JA

Cell systems 20190102 1

Metabolic adaptations accompanying the development of antibiotic resistance in bacteria remain poorly understood. To study this relationship, we profiled the growth of lab-evolved antibiotic-resistant lineages of the opportunistic pathogen Pseudomonas aeruginosa across 190 unique carbon sources. Our data revealed that the evolution of antibiotic resistance resulted in systems-level changes to growth dynamics and metabolic phenotype. A genome-scale metabolic network reconstruction of P. aeruginos ...[more]

PMID: 30611675

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Project description:Pseudomonas aeruginosa is an opportunistic human pathogen that has been a constant global health problem due to its ability to cause infection at different body sites and its resistance to a broad spectrum of clinically available antibiotics. The World Health Organization classified multidrug-resistant Pseudomonas aeruginosa among the top-ranked organisms that require urgent research and development of effective therapeutic options. Several approaches have been taken to achieve these goals, but they all depend on discovering potential drug targets. The large amount of data obtained from sequencing technologies has been used to create computational models of organisms, which provide a powerful tool for better understanding their biological behavior. In the present work, we applied a method to integrate transcriptome data with genome-scale metabolic networks of Pseudomonas aeruginosa. We submitted both metabolic and integrated models to dynamic simulations and compared their performance with published in vitro growth curves. In addition, we used these models to identify potential therapeutic targets and compared the results to analyze the assumption that computational models enriched with biological measurements can provide more selective and (or) specific predictions. Our results demonstrate that dynamic simulations from integrated models result in more accurate growth curves and flux distribution more coherent with biological observations. Moreover, identifying drug targets from integrated models is more selective as the predicted genes were a subset of those found in the metabolic models. Our analysis resulted in the identification of 26 non-host homologous targets. Among them, we highlighted five top-ranked genes based on lesser conservation with the human microbiome. Overall, some of the genes identified in this work have already been proposed by different approaches and (or) are already investigated as targets to antimicrobial compounds, reinforcing the benefit of using integrated models as a starting point to selecting biologically relevant therapeutic targets.

Dataset Information

Integrated Experimental and Computational Analyses Reveal Differential Metabolic Functionality in Antibiotic-Resistant Pseudomonas aeruginosa.

Publications

Integrated Experimental and Computational Analyses Reveal Differential Metabolic Functionality in Antibiotic-Resistant Pseudomonas aeruginosa.

Similar Datasets

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