Global Regulators in a Bacterial Pathogen and Virulence

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Bacteria colonise almost every niche on earth and they have been thriving for billions of years. Biologists believe that the 'success' of bacterial life on earth is due to the ability of bacteria to express the right gene at the right time, thereby making the most of the particular environment where they are growing. To do this, they selectively express the necessary genes in any situation, and one of the main ways they do this is by the use of transcription factors. These are a specialised group of proteins, which, in response to a particular signal from the environment, interact at the regulatory region of specific genes, and either turn on or turn off their expression. Some bacteria are able to colonise humans and a small number of these cause disease. To a bacterium, a human host is "just" another environment, and, hence, thriving in a human environment requires the expression of certain genes whose expression is regulated by transcription factors. Most transcription factors affect the expression of just a handful of genes, however a small number affect hundreds of genes, one of the most well-known being the transcription factor called CRP. Working with common bacterial pathogens that cause human disease, we have found that CRP controls some of the genes responsible for disease. One of our main aims is to follow up on this observation and identify the full catalogue of genes that are regulated by CRP in these pathogens. We expect to find hundreds of targets, and so a second aim is to understand how CRP is distributed between these targets, and how this alters in response to changes in the environment. Some very recent research suggests the existence of other proteins that interact with CRP and alter its activity at the regulatory region of certain genes. We will pay particular attention to the genes that make bacteria dangerous to humans. Antibiotics are commonly used to treat harmful infections due to bacteria, but it is well-known that there is currently a big problem due to the appearance of resistant bacteria that are not killed by antibiotics. Hence, there is a need to find new antibacterial strategies that do not rely on antibiotics. In previous work with CRP, we have been able to construct a version of CRP (CRP-0) that has lost its ability to regulate gene expression, but is able to interfere with the activity of 'good' CRP in harmful bacteria. Some preliminary data has shown that we can use CRP-0 to 'disarm' a harmful bacterial strain and make it harmless. We plan to develop a vector for the delivery of CRP-0 and, because CRP is so widespread in bacteria, this will provide an option to 'neutralise' many different bacterial pathogens by 'disarming' them rather than killing them, thereby providing a therapy option. Previous research has shown that most bacteria that contain CRP also contain a second very similar transcription factor called FNR. FNR is important to allow bacteria to adapt to growth in the absence of oxygen, and we have found that, for some bacterial pathogens, infection is aided by the absence of oxygen. Hence, we plan to take a parallel approach with FNR, and identify its targets. Comparison of targets between harmful and harmless bacteria should tell us why the lack of oxygen promotes virulence. In addition, FNR derivatives which, like CRP-0, are handicapped in their ability to regulate gene expression, will provide us with a second option to interfere with the expression of bacterial genes that are needed for successful infection. Hence, our overall strategy is to discover the contribution of CRP and FNR to bacterial infections and to exploit what we find to pioneer an anti-bacterial strategy that does not depend on antibiotics.