Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in <i>Streptococcus pneumoniae</i>
<i>Streptococcus pneumoniae</i> (Spn), a Gram-positive bacterium, poses a significant threat to human health, causing mild respiratory infections to severe invasive conditions. Despite the availability of vaccines, challenges persist due to serotype replacement and antibiotic resistance,...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/14/2/178 |
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| author | Moses B. Ayoola Leslie A. Shack Otto Phanstiel Bindu Nanduri |
| author_facet | Moses B. Ayoola Leslie A. Shack Otto Phanstiel Bindu Nanduri |
| author_sort | Moses B. Ayoola |
| collection | DOAJ |
| description | <i>Streptococcus pneumoniae</i> (Spn), a Gram-positive bacterium, poses a significant threat to human health, causing mild respiratory infections to severe invasive conditions. Despite the availability of vaccines, challenges persist due to serotype replacement and antibiotic resistance, emphasizing the need for alternative therapeutic strategies. This study explores the intriguing role of polyamines, ubiquitous, small organic cations, in modulating virulence factors, especially the capsule, a crucial determinant of Spn’s pathogenicity. Using chemical inhibitors, difluoromethylornithine (DFMO) and AMXT 1501, this research unveils distinct regulatory effects on the gene expression of the Spn D39 serotype in response to altered polyamine homeostasis. DFMO inhibits polyamine biosynthesis, disrupting pathways associated with glucose import and the interconversion of sugars. In contrast, AMXT 1501, targeting polyamine transport, enhances the expression of polyamine and glucose biosynthesis genes, presenting a novel avenue for regulating the capsule independent of glucose availability. Despite ample glucose availability, AMXT 1501 treatment downregulates the glycolytic pathway, fatty acid synthesis, and ATP synthase, crucial for energy production, while upregulating two-component systems responsible for stress management. This suggests a potential shutdown of energy production and capsule biosynthesis, redirecting resources towards stress management. Following DFMO and AMXT 1501 treatments, countermeasures, such as upregulation of stress response genes and ribosomal protein, were observed but appear to be insufficient to overcome the deleterious effects on capsule production. This study highlights the complexity of polyamine-mediated regulation in <i>S. pneumoniae</i>, particularly capsule biosynthesis. Our findings offer valuable insights into potential therapeutic targets for modulating capsules in a polyamine-dependent manner, a promising avenue for intervention against <i>S. pneumoniae</i> infections. |
| first_indexed | 2024-03-07T22:40:52Z |
| format | Article |
| id | doaj.art-9bfa8e5342f44245a2a6fcb1e0ab53c4 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-07T22:40:52Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-9bfa8e5342f44245a2a6fcb1e0ab53c42024-02-23T15:09:18ZengMDPI AGBiomolecules2218-273X2024-02-0114217810.3390/biom14020178Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in <i>Streptococcus pneumoniae</i>Moses B. Ayoola0Leslie A. Shack1Otto Phanstiel2Bindu Nanduri3Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USADepartment of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USADepartment of Medical Education, College of Medicine, University of Central Florida, Orlando, FL 32826, USADepartment of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA<i>Streptococcus pneumoniae</i> (Spn), a Gram-positive bacterium, poses a significant threat to human health, causing mild respiratory infections to severe invasive conditions. Despite the availability of vaccines, challenges persist due to serotype replacement and antibiotic resistance, emphasizing the need for alternative therapeutic strategies. This study explores the intriguing role of polyamines, ubiquitous, small organic cations, in modulating virulence factors, especially the capsule, a crucial determinant of Spn’s pathogenicity. Using chemical inhibitors, difluoromethylornithine (DFMO) and AMXT 1501, this research unveils distinct regulatory effects on the gene expression of the Spn D39 serotype in response to altered polyamine homeostasis. DFMO inhibits polyamine biosynthesis, disrupting pathways associated with glucose import and the interconversion of sugars. In contrast, AMXT 1501, targeting polyamine transport, enhances the expression of polyamine and glucose biosynthesis genes, presenting a novel avenue for regulating the capsule independent of glucose availability. Despite ample glucose availability, AMXT 1501 treatment downregulates the glycolytic pathway, fatty acid synthesis, and ATP synthase, crucial for energy production, while upregulating two-component systems responsible for stress management. This suggests a potential shutdown of energy production and capsule biosynthesis, redirecting resources towards stress management. Following DFMO and AMXT 1501 treatments, countermeasures, such as upregulation of stress response genes and ribosomal protein, were observed but appear to be insufficient to overcome the deleterious effects on capsule production. This study highlights the complexity of polyamine-mediated regulation in <i>S. pneumoniae</i>, particularly capsule biosynthesis. Our findings offer valuable insights into potential therapeutic targets for modulating capsules in a polyamine-dependent manner, a promising avenue for intervention against <i>S. pneumoniae</i> infections.https://www.mdpi.com/2218-273X/14/2/178<i>Streptococcus pneumoniae</i>polyamineDFMOAMXT 1501capsule |
| spellingShingle | Moses B. Ayoola Leslie A. Shack Otto Phanstiel Bindu Nanduri Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in <i>Streptococcus pneumoniae</i> Biomolecules <i>Streptococcus pneumoniae</i> polyamine DFMO AMXT 1501 capsule |
| title | Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in <i>Streptococcus pneumoniae</i> |
| title_full | Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in <i>Streptococcus pneumoniae</i> |
| title_fullStr | Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in <i>Streptococcus pneumoniae</i> |
| title_full_unstemmed | Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in <i>Streptococcus pneumoniae</i> |
| title_short | Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in <i>Streptococcus pneumoniae</i> |
| title_sort | impact of difluoromethylornithine and amxt 1501 on gene expression and capsule regulation in i streptococcus pneumoniae i |
| topic | <i>Streptococcus pneumoniae</i> polyamine DFMO AMXT 1501 capsule |
| url | https://www.mdpi.com/2218-273X/14/2/178 |
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