Redox Imbalance Underlies the Fitness Defect Associated with Inactivation of the Pta-AckA Pathway in <i>Staphylococcus aureus</i>

Marshall, Darrell D.; Sadykov, Marat R.; Thomas, Vinai Chittezham; Bayles, Kenneth W.; Powers, Robert

doi:10.1021/acs.jproteome.5b01089

Cited by 28 publications

(34 citation statements)

References 46 publications

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“…A redox imbalance can impact on the fitness of bacteria33. As the transcriptome analysis indicated a lower abundance of some nuo transcripts as well as of other transcripts encoding dehydrogenases ( glpD ; lldA ; lldD; Supplementary Table S2b) in the absence of Hfq, we next asked whether Hfq affects the intracellular NADH/NAD + ratio.…”

Section: Resultsmentioning

confidence: 99%

Cross-regulation by CrcZ RNA controls anoxic biofilm formation in Pseudomonas aeruginosa

Pušić

Tata

Wolfinger

et al. 2016

Sci Rep

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Pseudomonas aeruginosa (PA) can thrive in anaerobic biofilms in the lungs of cystic fibrosis (CF) patients. Here, we show that CrcZ is the most abundant PA14 RNA bound to the global regulator Hfq in anoxic biofilms grown in cystic fibrosis sputum medium. Hfq was crucial for anoxic biofilm formation. This observation complied with an RNAseq based transcriptome analysis and follow up studies that implicated Hfq in regulation of a central step preceding denitrification. CrcZ is known to act as a decoy that sequesters Hfq during relief of carbon catabolite repression, which in turn alleviates Hfq-mediated translational repression of catabolic genes. We therefore inferred that CrcZ indirectly impacts on biofilm formation by competing for Hfq. This hypothesis was supported by the findings that over-production of CrcZ mirrored the biofilm phenotype of the hfq deletion mutant, and that deletion of the crcZ gene augmented biofilm formation. To our knowledge, this is the first example where competition for Hfq by CrcZ cross-regulates an Hfq-dependent physiological process unrelated to carbon metabolism.

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Section: Resultsmentioning

confidence: 99%

Cross-regulation by CrcZ RNA controls anoxic biofilm formation in Pseudomonas aeruginosa

Pušić

Tata

Wolfinger

et al. 2016

Sci Rep

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“…A number of studies have attempted to explore the metabolic aspects of antimicrobial functionality of MRSA, including nitric oxide metabolism, oxidative stress, carbon overflow metabolism, redox imbalance etc. [6][7][8][9][10][11] However, a complete mechanistic understanding of staphylococcal metabolism is still missing, making the identification of therapeutic targets challenging.…”

Section: Introductionmentioning

confidence: 99%

“…Several other studies have been dedicated to elucidating the metabolic aspects of staphylococcal virulence and to pinpoint the key metabolic "hubs" in carbon and nitrogen metabolism. 11,[27][28][29][30][31][32] However, a majority of these studies were focused on specific segments of staphylococcal metabolism and overlooked a systemwide interdependence that drives fitness, metabolic robustness, virulence, and antimicrobial resistance. Hence, a holistic approach of in silico genome-scale modeling and in vivo experimentation is crucial for gaining an improved mechanistic understanding of staphylococcal metabolism, and thereby, facilitating the development of novel therapeutic strategies to combat staphylococcal infections.…”

Section: Introductionmentioning

confidence: 99%

An integrated computational and experimental study to investigate Staphylococcus aureus metabolism

et al. 2020

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Staphylococcus aureus is a metabolically versatile pathogen that colonizes nearly all organs of the human body. A detailed and comprehensive knowledge of staphylococcal metabolism is essential to understand its pathogenesis. To this end, we have reconstructed and experimentally validated an updated and enhanced genome-scale metabolic model of S. aureus USA300_FPR3757. The model combined genome annotation data, reaction stoichiometry, and regulation information from biochemical databases and previous strain-specific models. Reactions in the model were checked and fixed to ensure chemical balance and thermodynamic consistency. To further refine the model, growth assessment of 1920 nonessential mutants from the Nebraska Transposon Mutant Library was performed, and metabolite excretion profiles of important mutants in carbon and nitrogen metabolism were determined. The growth and no-growth inconsistencies between the model predictions and in vivo essentiality data were resolved using extensive manual curation based on optimization-based reconciliation algorithms. Upon intensive curation and refinements, the model contains 863 metabolic genes, 1379 metabolites (including 1159 unique metabolites), and 1545 reactions including transport and exchange reactions. To improve the accuracy and predictability of the model to environmental changes, condition-specific regulation information curated from the existing knowledgebase was incorporated. These critical additions improved the model performance significantly in capturing gene essentiality, substrate utilization, and metabolite production capabilities and increased the ability to generate model-based discoveries of therapeutic significance. Use of this highly curated model will enhance the functional utility of omics data, and therefore, serve as a resource to support future investigations of S. aureus and to augment staphylococcal research worldwide.npj Systems Biology and Applications (2020) 6:3 ; https://doi.

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“…A number of studies have attempted to explore the metabolic aspects of antimicrobial functionality of MRSA, including nitric oxide metabolism, oxidative stress, carbon overflow metabolism, redox imbalance etc. 6-11 . However, a complete mechanistic understanding of staphylococcal metabolism is still missing, making the identification of systematic therapeutic targets challenging.…”

Section: Introductionmentioning

confidence: 99%

“…Several other studies have been dedicated to elucidating the metabolic aspects of staphylococcal virulence and to pinpoint the key metabolic “hubs” in carbon and nitrogen metabolism 11,27-32 . However, a majority of these studies were focused on specific segments of staphylococcal metabolism and overlooked a system-wide inter-dependence that drives fitness, metabolic robustness, virulence, and antimicrobial resistance.…”

Section: Introductionmentioning

confidence: 99%

An integrated computational and experimental study to elucidateStaphylococcus aureusmetabolism

Islam

Thomas

Beek

et al. 2019

Preprint

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23Staphylococcus aureus is a metabolically versatile pathogen that colonizes nearly all organs of 24 the human body. A detailed and comprehensive knowledge of staphylococcal metabolism is 25 essential to understanding its pathogenesis. To this end, we have reconstructed and 26 experimentally validated an updated and enhanced genome-scale metabolic model of S. aureus 27 USA300_FPR3757. The model combined genome annotation data, reaction stoichiometry, and 28 regulation information from biochemical databases and previous strain-specific models. 29 Reactions in the model were checked and fixed to ensure chemical balance and thermodynamic 30 consistency. To further refine the model, growth assessment of 1920 non-essential mutants from 31 the Nebraska Transposon Mutant Library was performed and metabolite excretion profiles of 32 important mutants in carbon and nitrogen metabolism were determined. The growth and no-33 growth inconsistencies between the model predictions and in vivo essentiality data were resolved 34 using extensive manual curation based on optimization-based reconciliation algorithms. Upon 35 intensive curation and refinements, the model contains 840 metabolic genes, 1442 metabolites, 36 and 1566 reactions including transport and exchange reactions. To improve the accuracy and 37 predictability of the model to environmental changes, condition-specific regulation information 38 curated from the existing knowledgebase was incorporated. These critical additions improved the 39 model performance significantly in capturing gene essentiality, substrate utilization, and 40 metabolite production capabilities and increased the ability to generate model-based discoveries 41 of therapeutic significance. Use of this highly curated model will enhance the functional utility 42 of omics data and, therefore, serve as a resource to support future investigations of S. aureus and 43 to augment staphylococcal research worldwide. 44 45 3 Keywords: Staphylococcus aureus, genome-scale metabolic model 46 109 Results 110 Reconstruction of an updated model of S. aureus metabolism 111 Preliminary reconstruction utilizing the existing knowledge base 112 A collection of 1511 metabolic reactions obtained from a consensus of recently published strain-113 specific models 19,21 was assembled into a preliminary model of S. aureus. Out of 842 genes in 114 6 the latest strain-specific USA300_FPR3757_uid58555 model by Bosi et al. 19 , 109 did not have 115 any reactions associated with them, which were not included in our model at this stage. Checking 116 reactions from the S. aureus N315 model iSB619 20 against the annotations of strain 117 USA300_FPR3757 in the KEGG database 39 resulted in the inclusion of seven unique reactions to 118 the preliminary model. In addition, every metabolic function in the model was verified for 119 correct gene annotations in the NCBI, KEGG, and UniProt databases and published 120 resources 19,39-42 to amend the model with 38 metabolic reactions and annotate 75 additional 121 reactions with correct Gene-Pr...

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Redox Imbalance Underlies the Fitness Defect Associated with Inactivation of the Pta-AckA Pathway in Staphylococcus aureus

Cited by 28 publications

References 46 publications

Cross-regulation by CrcZ RNA controls anoxic biofilm formation in Pseudomonas aeruginosa

Cross-regulation by CrcZ RNA controls anoxic biofilm formation in Pseudomonas aeruginosa

An integrated computational and experimental study to investigate Staphylococcus aureus metabolism

An integrated computational and experimental study to elucidateStaphylococcus aureusmetabolism

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