Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production
The obligate anaerobe, spore forming bacterium Clostridioides difficile (formerly Clostridium difficile) causes nosocomial and community acquired diarrhea often associated with antibiotic therapy. Major virulence factors of the bacterium are the two large clostridial toxins TcdA and TcdB. The produc...
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| Format: | Article |
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Frontiers Media S.A.
2018-08-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2018.01970/full |
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| author | Julia D. Hofmann Julia D. Hofmann Andreas Otto Mareike Berges Mareike Berges Rebekka Biedendieck Rebekka Biedendieck Annika-Marisa Michel Annika-Marisa Michel Dörte Becher Dieter Jahn Dieter Jahn Meina Neumann-Schaal Meina Neumann-Schaal Meina Neumann-Schaal |
| author_facet | Julia D. Hofmann Julia D. Hofmann Andreas Otto Mareike Berges Mareike Berges Rebekka Biedendieck Rebekka Biedendieck Annika-Marisa Michel Annika-Marisa Michel Dörte Becher Dieter Jahn Dieter Jahn Meina Neumann-Schaal Meina Neumann-Schaal Meina Neumann-Schaal |
| author_sort | Julia D. Hofmann |
| collection | DOAJ |
| description | The obligate anaerobe, spore forming bacterium Clostridioides difficile (formerly Clostridium difficile) causes nosocomial and community acquired diarrhea often associated with antibiotic therapy. Major virulence factors of the bacterium are the two large clostridial toxins TcdA and TcdB. The production of both toxins was found strongly connected to the metabolism and the nutritional status of the growth environment. Here, we systematically investigated the changes of the gene regulatory, proteomic and metabolic networks of C. difficile 630Δerm underlying the adaptation to the non-growing state in the stationary phase. Integrated data from time-resolved transcriptome, proteome and metabolome investigations performed under defined growth conditions uncovered multiple adaptation strategies. Overall changes in the cellular processes included the downregulation of ribosome production, lipid metabolism, cold shock proteins, spermine biosynthesis, and glycolysis and in the later stages of riboflavin and coenzyme A (CoA) biosynthesis. In contrast, different chaperones, several fermentation pathways, and cysteine, serine, and pantothenate biosynthesis were found upregulated. Focusing on the Stickland amino acid fermentation and the central carbon metabolism, we discovered the ability of C. difficile to replenish its favored amino acid cysteine by a pathway starting from the glycolytic 3-phosphoglycerate via L-serine as intermediate. Following the growth course, the reductive equivalent pathways used were sequentially shifted from proline via leucine/phenylalanine to the central carbon metabolism first to butanoate fermentation and then further to lactate fermentation. The toxin production was found correlated mainly to fluxes of the central carbon metabolism. Toxin formation in the supernatant was detected when the flux changed from butanoate to lactate synthesis in the late stationary phase. The holistic view derived from the combination of transcriptome, proteome and metabolome data allowed us to uncover the major metabolic strategies that are used by the clostridial cells to maintain its cellular homeostasis and ensure survival under starvation conditions. |
| first_indexed | 2024-12-12T19:15:03Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-302X |
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| last_indexed | 2024-12-12T19:15:03Z |
| publishDate | 2018-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Microbiology |
| spelling | doaj.art-d92d6334a7f84191858ee909c559e1232022-12-22T00:14:45ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2018-08-01910.3389/fmicb.2018.01970403778Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin ProductionJulia D. Hofmann0Julia D. Hofmann1Andreas Otto2Mareike Berges3Mareike Berges4Rebekka Biedendieck5Rebekka Biedendieck6Annika-Marisa Michel7Annika-Marisa Michel8Dörte Becher9Dieter Jahn10Dieter Jahn11Meina Neumann-Schaal12Meina Neumann-Schaal13Meina Neumann-Schaal14Department of Bioinformatics and Biochemistry, Technische Universität Braunschweig, Braunschweig, GermanyBraunschweig Integrated Centre of Systems Biology (BRICS), Braunschweig, GermanyDepartment for Microbial Proteomics, University of Greifswald, Greifswald, GermanyBraunschweig Integrated Centre of Systems Biology (BRICS), Braunschweig, GermanyInstitute of Microbiology, Technische Universität Braunschweig, Braunschweig, GermanyBraunschweig Integrated Centre of Systems Biology (BRICS), Braunschweig, GermanyInstitute of Microbiology, Technische Universität Braunschweig, Braunschweig, GermanyBraunschweig Integrated Centre of Systems Biology (BRICS), Braunschweig, GermanyInstitute of Microbiology, Technische Universität Braunschweig, Braunschweig, GermanyDepartment for Microbial Proteomics, University of Greifswald, Greifswald, GermanyBraunschweig Integrated Centre of Systems Biology (BRICS), Braunschweig, GermanyInstitute of Microbiology, Technische Universität Braunschweig, Braunschweig, GermanyDepartment of Bioinformatics and Biochemistry, Technische Universität Braunschweig, Braunschweig, GermanyBraunschweig Integrated Centre of Systems Biology (BRICS), Braunschweig, GermanyLeibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures, Braunschweig, GermanyThe obligate anaerobe, spore forming bacterium Clostridioides difficile (formerly Clostridium difficile) causes nosocomial and community acquired diarrhea often associated with antibiotic therapy. Major virulence factors of the bacterium are the two large clostridial toxins TcdA and TcdB. The production of both toxins was found strongly connected to the metabolism and the nutritional status of the growth environment. Here, we systematically investigated the changes of the gene regulatory, proteomic and metabolic networks of C. difficile 630Δerm underlying the adaptation to the non-growing state in the stationary phase. Integrated data from time-resolved transcriptome, proteome and metabolome investigations performed under defined growth conditions uncovered multiple adaptation strategies. Overall changes in the cellular processes included the downregulation of ribosome production, lipid metabolism, cold shock proteins, spermine biosynthesis, and glycolysis and in the later stages of riboflavin and coenzyme A (CoA) biosynthesis. In contrast, different chaperones, several fermentation pathways, and cysteine, serine, and pantothenate biosynthesis were found upregulated. Focusing on the Stickland amino acid fermentation and the central carbon metabolism, we discovered the ability of C. difficile to replenish its favored amino acid cysteine by a pathway starting from the glycolytic 3-phosphoglycerate via L-serine as intermediate. Following the growth course, the reductive equivalent pathways used were sequentially shifted from proline via leucine/phenylalanine to the central carbon metabolism first to butanoate fermentation and then further to lactate fermentation. The toxin production was found correlated mainly to fluxes of the central carbon metabolism. Toxin formation in the supernatant was detected when the flux changed from butanoate to lactate synthesis in the late stationary phase. The holistic view derived from the combination of transcriptome, proteome and metabolome data allowed us to uncover the major metabolic strategies that are used by the clostridial cells to maintain its cellular homeostasis and ensure survival under starvation conditions.https://www.frontiersin.org/article/10.3389/fmicb.2018.01970/fullClostridium difficileClostridioides difficilemetabolismtoxin formationstarvationStickland reactions |
| spellingShingle | Julia D. Hofmann Julia D. Hofmann Andreas Otto Mareike Berges Mareike Berges Rebekka Biedendieck Rebekka Biedendieck Annika-Marisa Michel Annika-Marisa Michel Dörte Becher Dieter Jahn Dieter Jahn Meina Neumann-Schaal Meina Neumann-Schaal Meina Neumann-Schaal Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production Frontiers in Microbiology Clostridium difficile Clostridioides difficile metabolism toxin formation starvation Stickland reactions |
| title | Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production |
| title_full | Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production |
| title_fullStr | Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production |
| title_full_unstemmed | Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production |
| title_short | Metabolic Reprogramming of Clostridioides difficile During the Stationary Phase With the Induction of Toxin Production |
| title_sort | metabolic reprogramming of clostridioides difficile during the stationary phase with the induction of toxin production |
| topic | Clostridium difficile Clostridioides difficile metabolism toxin formation starvation Stickland reactions |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2018.01970/full |
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