Understanding how an antibiotic "warhead" is made by bacteria

细菌具有令人难以置信的能力来制造具有强大生物活性的分子，其中许多化合物在治疗各种疾病的现代医学中是不可或缺的。这些药物包括抗生素、抗真菌药物、抗炎药物、抗寄生虫药物和抗癌化合物。因此，我们想知道细菌是如何制造这些分子的，这样我们就可以设计它们的途径来制造新的生物活性化合物，并发现其他活性化合物的新途径。放线菌素是一种由土壤微生物链霉菌产生的多肽天然产物。值得注意的是，它是抗菌的，可以抑制肿瘤细胞的侵袭，阻止哺乳动物细胞的增殖，最近还被确定为抗疟疾候选药物。这种强大的生物活性源于它抑制金属蛋白酶的能力，这是由于一种可以紧密结合这些蛋白质的化学“弹头”。该项目的目的是了解这种关键弹头是如何由产生细菌自然地制造出来的，并利用这种了解来发现新的含有弹头的化合物。

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.