Structural basis of topoisomerase targeting by delafloxacin
Abstract Delafloxacin is a potent anionic fluoroquinolone approved for the treatment of respiratory infections that acts by trapping the DNA cleavage complexes of bacterial topoisomerase IV and gyrase. Its N-1-pyridinyl-, C-7-azetidinyl- and C-8-chlorine substituents confer enhanced antibiotic activ...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60688-3 |
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| author | Shabir Najmudin Xiao-Su Pan Beijia Wang Lata Govada Naomi E. Chayen Noelia Rubio Milo S. P. Shaffer Henry S. Rzepa L. Mark Fisher Mark R. Sanderson |
| author_facet | Shabir Najmudin Xiao-Su Pan Beijia Wang Lata Govada Naomi E. Chayen Noelia Rubio Milo S. P. Shaffer Henry S. Rzepa L. Mark Fisher Mark R. Sanderson |
| author_sort | Shabir Najmudin |
| collection | DOAJ |
| description | Abstract Delafloxacin is a potent anionic fluoroquinolone approved for the treatment of respiratory infections that acts by trapping the DNA cleavage complexes of bacterial topoisomerase IV and gyrase. Its N-1-pyridinyl-, C-7-azetidinyl- and C-8-chlorine substituents confer enhanced antibiotic activity against bacteria resistant to other fluoroquinolones, but its mode of action is unclear. Here we present the X-ray crystal structures of a delafloxacin-DNA cleavage complex obtained by co-crystallization with Streptococcus pneumoniae topo IV using a graphene nucleant and solved at 2.0 and 2.4 Å resolution. The two Mg2+-chelated delafloxacin molecules intercalated at the DNA cleavage site are bound in an unusual conformation involving interacting out-of-plane N-1-aromatic- and C-8-chlorine- substituents. The unprecedented resolution allows comprehensive imaging of water-metal ion links integrating enzyme and DNA through drug-bound and active-site Mg2+ ions plus the discovery of enzyme-bound K+ ions. Our studies on delafloxacin action suggest that intrinsic target affinity contributes to its activity against quinolone-resistant bacteria. |
| format | Article |
| id | doaj-art-9951fe05aa794aed88923fcaebffc981 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9951fe05aa794aed88923fcaebffc9812025-08-20T03:45:33ZengNature PortfolioNature Communications2041-17232025-07-0116111510.1038/s41467-025-60688-3Structural basis of topoisomerase targeting by delafloxacinShabir Najmudin0Xiao-Su Pan1Beijia Wang2Lata Govada3Naomi E. Chayen4Noelia Rubio5Milo S. P. Shaffer6Henry S. Rzepa7L. Mark Fisher8Mark R. Sanderson9Molecular and Cellular Sciences Section, Neuroscience and Cell Biology Research Institute, City St George’s, University of London, Cranmer TerraceMolecular and Cellular Sciences Section, Neuroscience and Cell Biology Research Institute, City St George’s, University of London, Cranmer TerraceDivision of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College LondonDivision of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College LondonDivision of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College LondonDepartments of Chemistry & Materials Science, Imperial College LondonDepartments of Chemistry & Materials Science, Imperial College LondonDepartment of Chemistry, Imperial College LondonMolecular and Cellular Sciences Section, Neuroscience and Cell Biology Research Institute, City St George’s, University of London, Cranmer TerraceMolecular and Cellular Sciences Section, Neuroscience and Cell Biology Research Institute, City St George’s, University of London, Cranmer TerraceAbstract Delafloxacin is a potent anionic fluoroquinolone approved for the treatment of respiratory infections that acts by trapping the DNA cleavage complexes of bacterial topoisomerase IV and gyrase. Its N-1-pyridinyl-, C-7-azetidinyl- and C-8-chlorine substituents confer enhanced antibiotic activity against bacteria resistant to other fluoroquinolones, but its mode of action is unclear. Here we present the X-ray crystal structures of a delafloxacin-DNA cleavage complex obtained by co-crystallization with Streptococcus pneumoniae topo IV using a graphene nucleant and solved at 2.0 and 2.4 Å resolution. The two Mg2+-chelated delafloxacin molecules intercalated at the DNA cleavage site are bound in an unusual conformation involving interacting out-of-plane N-1-aromatic- and C-8-chlorine- substituents. The unprecedented resolution allows comprehensive imaging of water-metal ion links integrating enzyme and DNA through drug-bound and active-site Mg2+ ions plus the discovery of enzyme-bound K+ ions. Our studies on delafloxacin action suggest that intrinsic target affinity contributes to its activity against quinolone-resistant bacteria.https://doi.org/10.1038/s41467-025-60688-3 |
| spellingShingle | Shabir Najmudin Xiao-Su Pan Beijia Wang Lata Govada Naomi E. Chayen Noelia Rubio Milo S. P. Shaffer Henry S. Rzepa L. Mark Fisher Mark R. Sanderson Structural basis of topoisomerase targeting by delafloxacin Nature Communications |
| title | Structural basis of topoisomerase targeting by delafloxacin |
| title_full | Structural basis of topoisomerase targeting by delafloxacin |
| title_fullStr | Structural basis of topoisomerase targeting by delafloxacin |
| title_full_unstemmed | Structural basis of topoisomerase targeting by delafloxacin |
| title_short | Structural basis of topoisomerase targeting by delafloxacin |
| title_sort | structural basis of topoisomerase targeting by delafloxacin |
| url | https://doi.org/10.1038/s41467-025-60688-3 |
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