A reconstructed genome-scale metabolic model of Helicobacter pylori for predicting putative drug targets in clarithromycin and rifampicin resistance conditions
Sepideh Mofidifar
Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
Search for more papers by this authorCorresponding Author
Abbas Yadegar
Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Correspondence
Abbas Yadegar, Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Shahid Arabi Ave., Yemen St., Velenjak, Tehran, Iran.
Email: a.yadegar@sbmu.ac.ir; babak_y1983@yahoo.com
Mohammad Hossein Karimi-Jafari, Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Email: mhkarimijafari@ut.ac.ir
Search for more papers by this authorCorresponding Author
Mohammad Hossein Karimi-Jafari
Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
Correspondence
Abbas Yadegar, Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Shahid Arabi Ave., Yemen St., Velenjak, Tehran, Iran.
Email: a.yadegar@sbmu.ac.ir; babak_y1983@yahoo.com
Mohammad Hossein Karimi-Jafari, Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Email: mhkarimijafari@ut.ac.ir
Search for more papers by this authorSepideh Mofidifar
Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
Search for more papers by this authorCorresponding Author
Abbas Yadegar
Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Correspondence
Abbas Yadegar, Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Shahid Arabi Ave., Yemen St., Velenjak, Tehran, Iran.
Email: a.yadegar@sbmu.ac.ir; babak_y1983@yahoo.com
Mohammad Hossein Karimi-Jafari, Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Email: mhkarimijafari@ut.ac.ir
Search for more papers by this authorCorresponding Author
Mohammad Hossein Karimi-Jafari
Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
Correspondence
Abbas Yadegar, Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Shahid Arabi Ave., Yemen St., Velenjak, Tehran, Iran.
Email: a.yadegar@sbmu.ac.ir; babak_y1983@yahoo.com
Mohammad Hossein Karimi-Jafari, Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Email: mhkarimijafari@ut.ac.ir
Search for more papers by this authorAbstract
Background
Helicobacter pylori is considered a true human pathogen for which rising drug resistance constitutes a drastic concern globally. The present study aimed to reconstruct a genome-scale metabolic model (GSMM) to decipher the metabolic capability of H. pylori strains in response to clarithromycin and rifampicin along with identification of novel drug targets.
Materials and Methods
The iIT341 model of H. pylori was updated based on genome annotation data, and biochemical knowledge from literature and databases. Context-specific models were generated by integrating the transcriptomic data of clarithromycin and rifampicin resistance into the model. Flux balance analysis was employed for identifying essential genes in each strain, which were further prioritized upon being nonhomologs to humans, virulence factor analysis, druggability, and broad-spectrum analysis. Additionally, metabolic differences between sensitive and resistant strains were also investigated based on flux variability analysis and pathway enrichment analysis of transcriptomic data.
Results
The reconstructed GSMM was named as HpM485 model. Pathway enrichment and flux variability analyses demonstrated reduced activity in the ribosomal pathway in both clarithromycin- and rifampicin-resistant strains. Also, a significant decrease was detected in the activity of metabolic pathways of clarithromycin-resistant strain. Moreover, 23 and 16 essential genes were exclusively detected in clarithromycin- and rifampicin-resistant strains, respectively. Based on prioritization analysis, cyclopropane fatty acid synthase and phosphoenolpyruvate synthase were identified as putative drug targets in clarithromycin- and rifampicin-resistant strains, respectively.
Conclusions
We present a robust and reliable metabolic model of H. pylori. This model can predict novel drug targets to combat drug resistance and explore the metabolic capability of H. pylori in various conditions.
CONFLICT OF INTEREST STATEMENT
The authors have no conflicts of interest to declare.
Open Research
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
Supporting Information
| Filename | Description |
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| hel13074-sup-0001-FigureS1.docxWord 2007 document , 279.7 KB |
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| hel13074-sup-0002-FigureS2.docxWord 2007 document , 313.2 KB |
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| hel13074-sup-0003-TableS1.docxWord 2007 document , 29.4 KB |
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| hel13074-sup-0004-TableS2.docxWord 2007 document , 37 KB |
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| hel13074-sup-0005-FileS1.xlsxExcel 2007 spreadsheet , 28.9 KB |
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| hel13074-sup-0006-FileS2.xlsxExcel 2007 spreadsheet , 66 KB |
Supplementary file 2. |
| hel13074-sup-0007-FileS3.xlsxExcel 2007 spreadsheet , 63.9 KB |
Supplementary file 3. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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