Kistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics
Kistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics
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DOI：
10.1038/s41467-019-10384-w
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发表时间：
2019-06-13
影响因子：
16.6
通讯作者：
Cryle, Max J.
中科院分区：
文献类型：
--
作者：
Greule, Anja;Izore, Thierry;Cryle, Max J.
Kistamicin 是糖肽抗生素的不同成员，糖肽抗生素是一类结构复杂的重要临床相关抗生素，通常用作对抗耐药细菌的最后手段。这些抗生素的广泛交联结构对其活性至关重要，这使得它们的化学合成极具挑战性，并限制了它们的生产只能通过细菌发酵进行。 Kistamicin 含有三个交联，包括一个不寻常的 15 元 A-O-B 环，尽管只有两种细胞色素 P450 Oxy 酶被认为可以催化生物合成基因簇内此类交联的形成。在这项研究中，我们描述了 kistamicin 环化途径，表明两种 Oxy 酶负责 kistamicin 内的这些交联，并且它们通过与 X 结构域的相互作用发挥作用，这是糖肽抗生素生物合成所特有的。我们还表明 kistamicin OxyC 酶是一种混杂的生物催化剂，能够在含有酚类氨基酸的肽中安装多个交联。
Kistamicin is a divergent member of the glycopeptide antibiotics, a structurally complex class of important, clinically relevant antibiotics often used as the last resort against resistant bacteria. The extensively crosslinked structure of these antibiotics that is essential for their activity makes their chemical synthesis highly challenging and limits their production to bacterial fermentation. Kistamicin contains three crosslinks, including an unusual 15-membered A-O-B ring, despite the presence of only two Cytochrome P450 Oxy enzymes thought to catalyse formation of such crosslinks within the biosynthetic gene cluster. In this study, we characterise the kistamicin cyclisation pathway, showing that the two Oxy enzymes are responsible for these crosslinks within kistamicin and that they function through interactions with the X-domain, unique to glycopeptide antibiotic biosynthesis. We also show that the kistamicin OxyC enzyme is a promiscuous biocatalyst, able to install multiple crosslinks into peptides containing phenolic amino acids.