Understanding and exploiting the Mce proteins from Streptomyces

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Streptomyces is a harmless soil bacterium that is often found around the roots of plants, interacting with them but without causing disease. Streptomyces also interacts with other soil organisms such as amoeba, single celled organisms that behave like the phagocytic cells in the human body, eating bacterial cells. Recently we were able to identify that a group of genes (the mce genes, which stands for Mammalian Cell Entry genes) that are found in Streptomyces and are very closely related to genes in its distant cousin Mycobacterium tuberculosis, the bacterium that causes TB. We showed that these mce genes in Streptomyces encode the components of an ABC transporter and six substrate binding proteins that are important for gathering nutrients from the environment. Yet in M. tuberculosis they are required for them to colonise human lung cells and grow within those cells. This studentship proposal is aimed at more detailed study of this mce transporter system so it can be exploited in the (bio)chemical industry. We will fully characterise this transport system at the protein level and study the molecular details of what substrates they bind and take up, and how this contributes to their biological role. The findings of this study will have implications for our understanding of how human and animal pathogens have evolved from non-pathogenic bacteria and how we can exploit these proteins as potential novel drug and vaccine targets for pathogens. Recently it has been found that homologues of these Mce proteins are present in Gram-negative bacteria and excitingly are essential for growth and survival. This opens up the possibility that a deeper understanding of their function can help develop drugs against a whole range of bacterial pathogens which are currently causing concern due to the rise of antimicrobial resistant strains. This protein family is very diverse and there are also possibilities that they can be used in the biotechnology/biocatalysis industry to help make useful drugs, such as steroids from plant waste products by increasing the transport of hydrophobic substrates such as sterols that can then be biotransformed within bacterial cells. This highlights the importance of this protein family and that their study has implications for human health and industrial biotechnology. This studentship proposal has four main objectives that are linked to our overall aim of understanding and exploiting the mce genes from Streptomyces 1) To determine the level of functional redundancy in the Streptomyces mce locus - i.e. why are there multiple copies of Mce substrate proteins and does this reflect increased substrate binding capability and metabolic versatility?2) To fully characterise the regulation of mce proteins from Streptomyces using RNASeq.3) To understand the transport mechanism of substrates via the Mce transporter4) To develop the use of Mce proteins for biocataysis and biotransformation