Research reveals how new pneumonia drug fights infection

A new crystallisation method has achieved a record high X-ray resolution, revealing how a novel fluoroquinolone antibiotic works.

“With high quality crystals, we managed to solve an unprecedentedly high-resolution structure of a delafloxacin-bound topoisomerase complex” Beijia Wang Department of Metabolism, Digestion and Reproduction Research Postgraduate and joint first author

Researchers from Imperial have used a new crystallisation promoter to produce crystals diffracting  X-rays to unprecedentedly high resolution, which has provided insight into the action of a novel fluoroquinolone antibacterial drug.

Fluoroquinolones are a class of clinically used antibacterial drugs; the most recently approved member is Delafloxacin. This class of antibacterials targets bacterial DNA-topoisomerase IV complexes, a key bacterial enzyme complex that unknots and separates newly-synthesised DNA during bacterial replication. Fluoroquinolones disrupt this bacterial replication process and lead to bacterial cell death.

The researchers recently reported in PNAS the location and identity of metal ions in topoisomerase IV that are crucial for the function and structure of this enzyme. The findings of this study take the information several steps further.

The new findings solved a high-resolution structure, which provided details of a water network essential for bridging the drug to the enzyme through metal ion-water linkage. Furthermore, it could define the drug binding site extremely clearly, providing clues to explain delafloxacin's enhanced potency against resistant bacterial strains. These key findings can also be used to facilitate the design of future antimicrobials.

Professor Naomi Chayen, from Imperial's Department of Metabolism, Digestion and Reproduction, said: “The success of this study was made possible by applying a special nucleating agent which resulted in the highest resolution crystals ever produced for this complex.” 

The research centres on topoisomerases from the Streptococcus pneumoniae, a leading causative bacterium for a number of life-threatening medical conditions, including pneumococcal pneumonia. Pneumococcal pneumonia is a major global health burden, affecting primarily children under the age of 5, with an estimated global mortality of over 1 million. The emergence of antimicrobial resistance has presented a key challenge for tackling pneumococcal pneumonia. 

Professors Henry Rzepa and Mark Sanderson added: “Quantum mechanical calculations with Gaussian 16 has allowed us to study the conformation of Delafloxacin prior to binding to the DNA-topoisomerase IV complex.”

The research, published in Nature Communications, was performed by Professor Naomi Chayen’s Team (Department of Metabolism, Digestion and Reproduction) in collaboration with Professor Milo Shaffer’s Team (Department of Chemistry and Material Science, Imperial College), Professor Henry Rzepa (Dept of Chemistry, Imperial College) and City St George’s, University of London. It was co-led by Imperial’s Professor Mark Sanderson and Professor Mark Fisher from City St George’s. 

This research was supported by the Medical Research Council (MRC).

Najmudin, S., Pan, XS., Wang, B. et al. Structural basis of topoisomerase targeting by delafloxacin. Nat Commun 16, 5829 (2025). https://doi.org/10.1038/s41467-025-60688-3