Researchers from City St George’s, University of London, have made a breakthrough in the fight against drug-resistant bacteria. Using a novel X-ray scattering technique, they have precisely identified the location and composition of metal ions in bacteria that are crucial for antibiotics to work effectively. This discovery could lead to the development of new antibacterial drugs targeting topoisomerase IV, a key enzyme in bacterial cell division, and potentially combat the growing problem of antibiotic resistance.
Bacterial Secrets Unwound
Bacteria are incredibly tough and well-adapted to resistance, its growing problem worldwide. It turns out that bacteria of many kinds make an enzyme, known as topoisomerase IV, that is vitally important for the cells to reproduce. The enzyme sits down and pulls apart the replicated DNA in the complex, crowded surroundings of bacterial cells, so they can split in two during cell division.
One target, the topoisomerase IV complex that facilitates DNA unwinding and isomerization during bacterial cell division, is bound by antibiotics including fluoroquinolones, such as delafloxacin. But a deeper understanding of how this happens has been frustratingly elusive — until now.
X-Ray Scattering Reveals All
Using a revolutionary X-ray scattering technique, a research team lead by Professor Mark Fisher from the Neuroscience and Cell Biology Research Institute at City St George’s, University of London has unlocked the secrets of the topoisomerase IV complex. The researchers used X-ray beams at two different energies to pinpoint the precise position of the magnesium ions that are paired with both the drug and the enzyme and must be present for topoisomerase IV to operate correctly.
However, as the researchers went on to find out, potassium and chloride ions were also present in the enzyme complex. This discovery, which is a world-first, generates new knowledge of the complex interactions between metal ions that are essential for topoisomerase IV to do its central chore in bacterial cell division.
Antibiotic Discovery Spawns New Pathways
This had utterly profound implications. Scientists have laid the groundwork for new antibiotic compounds that could pinpoint metal ions inside a bacterium, thereby rioting out topoisomerases from bacteria.
Professor Fisher said: “A lot of enzymes that bacteria require to grow and many drugs that kill bacteria need metal ions for their activities. Dr. Martin Högbom from the Department of Biochemistry and Biophysics (left image) and Dr. Saem Khan from Uppsala University’s Department of Chemistry Ångström Laboratory researched the enzyme by using X-ray scattering to capture images like those shown in an updated model of a [Fe-Fe] hydrogenase cluster that each contains two metals in its active site.
With this knowledge, it may be possible to develop more specific and efficacious antibacterial drugs that can help alleviate the increasingly serious problem of drug-resistant diseases like pneumococcal pneumonia, a major killer among children worldwide. The research suggests the work could have broad implications among many varieties of potentially deadly bacterial infections.
