8C41

High resolution structure of the Streptococcus pneumoniae topoisomerase IV-DNA complex with the novel fluoroquinolone Delafloxacin

Summary for 8C41

• Entry DOI: 10.2210/pdb8c41/pdb
• Descriptor: Fused ParE30ParC55 CLEAVAGE COMPLEX of the TOPOISOMERASE IV, DNA (5'-D(*CP*AP*TP*GP*AP*AP*T)-3'), DNA (5'-D(P*AP*GP*TP*CP*AP*TP*TP*CP*AP*TP*G)-3'), ... (10 entities in total)
• Functional Keywords: protein-dna cleavage complex, topoisomerase iia, delafloxacin, topoisomerase iv-dna-antibiotic complex, isomerase
• Biological source: Streptococcus pneumoniae; More
• Total number of polymer chains: 6
• Total formula weight: 180816.89

Authors

Najmudin, S.,Pan, X.S.,Wang, B.,Chayen, N.E.,Fisher, L.M.,Sanderson, M.R. (deposition date: 2022-12-30, release date: 2024-01-10, Last modification date: 2025-07-23)

Primary citation

Najmudin, S.,Pan, X.S.,Wang, B.,Govada, L.,Chayen, N.E.,Rubio, N.,Shaffer, M.S.P.,Rzepa, H.S.,Fisher, L.M.,Sanderson, M.R.
Structural basis of topoisomerase targeting by delafloxacin.
Nat Commun, 16:5829-5829, 2025

PubMed 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 Mg-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 Mg 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.

PubMed: 40595483
DOI: 10.1038/s41467-025-60688-3

Experimental method

X-RAY DIFFRACTION (2.393 Å)