X-ray scattering pinpoints new targets for antibiotics

UK scientists have used a new ultrahigh-precision X-ray scattering technique to unveil the location and identity of metal ions in bacteria that are crucial for antibiotics to work optimally. Their work has been published in the journal PNAS.

Many types of bacteria produce an enzyme molecule called topoisomerase IV, which disentangles and separates newly replicated DNA in complex structures within bacteria to enable the cells to divide and multiply. Antibacterial drugs called fluoroquinolones, such as delafloxacin, seek out magnesium ions and bind to this complex structure. Once bound, the drug blocks the topoisomerase from working, and ultimately prevents bacterial cells from multiplying.

X-ray scattering investigates the amount of energy produced by metal ions when an X-ray beam is applied. The change in energy released when X-ray beams of different energies are used reveals the identity of different metal ions and where they reside in biological structures.

By using X-ray beams at two defined energies, the research team from Imperial College London, City St George’s, University of London and Diamond Light Source determined the exact location of drug- and enzyme-bound magnesium ions, and identified the presence of potassium and chloride ions in the enzyme complex.

The researchers said their breakthrough could initiate the development of new antibacterial drugs for an array of diseases. Indeed, at the Diamond Light Source synchrotron, X-rays from the I23 beamline provided new insights on the delafloxacin-bound topoisomerase IV of Streptococcus pneumoniae, a bacterium which is the main cause of community-acquired pneumonia and causes other life-threatening diseases including meningitis and sepsis.

“Many enzymes and important drugs that kill bacteria are dependent on metal ions for their activities,” said Professor Mark Fisher, from the City St George’s Neuroscience and Cell Biology Research Institute. “Our breakthrough using X-ray scattering has unveiled metal ion identities and locations more precisely than before and should be the springboard for new advancements in enzymology and drug development.

“This greater understanding of fluoroquinolones, their topoisomerase targets and the role of magnesium, potassium and chloride ions will hopefully aid the design of drugs to counter the growing problem of drug-resistant diseases.”

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