Understanding how an antibiotic "warhead" is made by bacteria

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Bacteria have an incredible ability to make molecules that have potent biological activity, and many of these compounds are indispensable in modern medicine for the treatment of various diseases. These medicines include antibiotics, antifungals, anti-inflammatories, antiparasitics and anti-cancer compounds. We therefore want to know how bacteria make these molecules so we can engineer their pathways to make new biologically active compounds, and discover new pathways to other active compounds.Actinonin is a peptide natural product produced by a species of the soil-dwelling microbe Streptomyces. Remarkably, it is antibacterial, inhibits tumour cell invasion, blocks mammalian cell proliferation and was also recently identified as an antimalarial candidate. This potent biological activity arises from its ability to inhibit metalloproteases, which is due to a chemical "warhead" that can tightly bind these proteins. The aim of this project is to understand how this critical warhead is made naturally by the producing bacterium, and to use this understanding to discover new warhead-containing compounds.