Structural basis of topoisomerase targeting by delafloxacin
Shabir Najmudin,
Xiao-Su Pan,
Beijia Wang,
Lata Govada,
Naomi E. Chayen,
Noelia Rubio,
Milo S. P. Shaffer,
Henry S. Rzepa,
L. Mark Fisher () and
Mark R. Sanderson ()
Additional contact information
Shabir Najmudin: Cranmer Terrace
Xiao-Su Pan: Cranmer Terrace
Beijia Wang: Imperial College London
Lata Govada: Imperial College London
Naomi E. Chayen: Imperial College London
Noelia Rubio: Imperial College London
Milo S. P. Shaffer: Imperial College London
Henry S. Rzepa: Imperial College London
L. Mark Fisher: Cranmer Terrace
Mark R. Sanderson: Cranmer Terrace
Nature Communications, 2025, vol. 16, issue 1, 1-15
Abstract:
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.
Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60688-3
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DOI: 10.1038/s41467-025-60688-3
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