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@article{Najmudin:2025:10.1038/s41467-025-60688-3,
author = {Najmudin, S and Pan, X-S and Wang, B and Govada, L and Chayen, N and Rubio, N and Shaffer, MSP and Rzepa, HS and Fisher, LM and Sanderson, M},
doi = {10.1038/s41467-025-60688-3},
journal = {Nature Communications},
title = {Structural basis of topoisomerase targeting by delafloxacin},
url = {http://dx.doi.org/10.1038/s41467-025-60688-3},
volume = {16},
year = {2025}
}
TY - JOUR
AB - 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.
AU - Najmudin,S
AU - Pan,X-S
AU - Wang,B
AU - Govada,L
AU - Chayen,N
AU - Rubio,N
AU - Shaffer,MSP
AU - Rzepa,HS
AU - Fisher,LM
AU - Sanderson,M
DO - 10.1038/s41467-025-60688-3
PY - 2025///
SN - 2041-1723
TI - Structural basis of topoisomerase targeting by delafloxacin
T2 - Nature Communications
UR - http://dx.doi.org/10.1038/s41467-025-60688-3
VL - 16
ER -