Understanding and Exploiting Tunicamycin (Bio)Synthesis to Enable Novel Antibiotics and Inhibitors

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Streptomyces are bacteria that live in the soil and produce antibiotics to compete with other soil microorganisms. Tunicamycin is an antibiotic made by Streptomyces chartreusis with a very unusual chemical structure. It kills other bacteria by blocking the action of a protein (an enzyme) that performs an essential role in making the walls of bacterial cells. These cell walls are essential for bacteria to survive. The way in which tunicamycin kills bacteria is different to almost all other antibiotics that are used in medicine and so tunicamycin has the potential to become a new and very effective antibacterial treatment to counter, for example, MRSA infections.The chemical structure of tunicamycin is actually similar to some of the building blocks used to make cell walls. This suggests that it may act my mimicking these building blocks, preventing the enzyme that makes cell walls from choosing the correct components. We have discovered recently the genes that allow S. chartreusis to make tunicamycin, and we can now use these genes to produce the enzymes that make tunicamycin. We have also developed methods to make the building blocks, and slightly different versions of them, that are used to make tunicamycin. As a consequence, we are now in a very good position to understand not only how the very unusual tunicamycin structure is made by S. chartreusis, but also to use the enzymes and the variant building blocks to generate new tunicamycin-like compounds. Ultimately we aim to genetically manipulate S. chartreusis itself to produce such compounds. Why is this important? Although tunicamycin is very good at killing bacteria, it also harms human cells, and so cannot be used as an antibiotic. By changing the structure of tunicamycin, we hope to remove the activity that is deleterious to humans, while retaining, or even improving, the activity against bacteria.