New Antibiotics Could Develop From a DNA Binding Compound

Researchers at the at the University of Warwick (Coventery, United Kingdom) discovered the new compound ([Fe2L3]4+), which is composed of an iron triple helicate with three organic strands wrapped around two iron centers, thus forming a helix which looks cylindrical in shape and neatly fits within the major groove of a DNA helix. When the iron-helicate binds to this major groove, it coils the DNA so that it is no longer available to bind to anything else, and is not able to drive biological or chemical processes. A high positive charge inherent in the compound enhances its ability to bind to DNA, which is negatively charged.

The researchers initially focused on the application of this useful property for targeting the DNA of cancer cells, since it could bind to, coil up, and shut down the cancer cell's DNA, thus killing the cell or stopping it replicate. However, the research team quickly realized that it might also be a very clever way of targeting drug-resistant bacteria; since it operates by targeting DNA; the iron helicate avoids all current resistance mechanisms of multiresistant bacteria such as methillicin resistant Streptococcus aureus (MRSA). Subsequently, they found that [Fe2L3]4+ does indeed have a powerful effect on bacteria; when introduced to two test bacteria (Bacillus subtilis and Escherichia coli), it quickly bound to the bacteria's DNA and killed virtually every cell within two minutes of being introduced (though the concentration required for this is high). The study was published in the June 2009 issue of the International Journal of Antimicrobial Agents.

"We were surprised at how quickly this compound killed bacteria and these results make this compound a key lead compound for researchers working on the development of novel antibiotics to target drug resistant bacteria,” said lead author Professor Alison Rodger, Ph.D., of the department of biophysical chemistry.

The researchers will next try to understand how and why the compound can cross the bacteria cell wall and membranes. They also plan to test a wide range of compounds to search for molecules similar to the iron helicate which posses the same mechanism for action, in collaboration with researchers around the world.

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