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

链霉菌是一种生活在土壤中的细菌，产生抗生素与其他土壤微生物竞争。Tunicamycin是一种由黄疸链霉菌产生的抗生素，具有非常不寻常的化学结构。它通过阻断一种蛋白质（一种酶）的作用来杀死其他细菌，这种蛋白质（一种酶）在细菌细胞壁的形成中起着至关重要的作用。这些细胞壁是细菌生存所必需的。tunicamycin杀死细菌的方式不同于几乎所有其他医学上使用的抗生素，因此tunicamycin有可能成为一种新的非常有效的抗菌治疗方法，例如对抗MRSA感染。tunicamycin的化学结构实际上类似于一些用来制造细胞壁的构件。这表明它可能模仿这些构建模块，阻止制造细胞壁的酶选择正确的成分。我们最近发现了允许黄曲霉菌制造衣霉素的基因，我们现在可以用这些基因来制造衣霉素的酶。我们还开发了一些方法来制造构建模块，以及它们的稍微不同的版本，用于制造衣霉素。因此，我们现在处于一个非常有利的位置，不仅可以了解金黄色葡萄球菌如何制造这种非常不寻常的衣霉素结构，而且可以利用这些酶和变体构建块来产生新的衣霉素样化合物。最终，我们的目标是通过基因操纵黄曲霉本身来产生这些化合物。为什么这很重要？尽管tunicamycin能很好地杀死细菌，但它也会伤害人体细胞，因此不能用作抗生素。通过改变衣霉素的结构，我们希望去除对人体有害的活性，同时保留甚至提高对细菌的活性。

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.