The Wbl proteins - a novel family of [4Fe-4S] cluster-containing transcription factors

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The harmless soil bacteria called streptomycetes are important to our welfare because they are the source of the vast majority of antibiotics used to cure infectious diseases, as well as providing us with numerous other medicines used, for example, to treat cancer, and to help organ transplant patients. We have identified two key regulators (called 'transcription factors') that switch the genetic machinery of these useful bacteria to allow them to reproduce themselves. We have discovered that these regulators are unusual in containing a special sensing device (called an 'iron-sulphur cluster') which likely controls reproduction of the bacteria in response to key environmental signals, like oxygen. In this grant we expect to find out exactly how these regulators work, to understand what they do in the cell and the role of the special sensing device (the 'iron-sulphur cluster'). We also know that similar key regulators are present in dangerous bacteria that cause important fatal diseases like tuberculosis and diphtheria. In the bacterium that causes tuberculosis, one of these regulators controls resistance to a wide range of antibiotics (a phenomenon called 'multi-drug resistance'). If we can understand how these regulators worked, we may be able to develop new medicines to target and eliminate multi-drug resistance, making it much easier to cure patients suffering from tuberculosis.