Discovery and biosynthesis of persiathiacins: Unusual polyglycosylated thiopeptides active against multi-drug resistant tuberculosis
Discovery and biosynthesis of persiathiacins: Unusual polyglycosylated thiopeptides active against multi-drug resistant tuberculosis
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DOI：
10.1101/2021.10.24.465558
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
Y. Dashti;F. Mohammadipanah;M. Belousoff;Anthony Vocat;Daniel Zabala;C. Fage;I. Romero‐Canelón;B. Bun
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文献类型：
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作者：
Y. Dashti;F. Mohammadipanah;M. Belousoff;Anthony Vocat;Daniel Zabala;C. Fage;I. Romero‐Canelón;B. Bun
硫肽是核糖体生物合成和后修饰的肽（RIPPs），其通过靶向蛋白质生物合成中的多个步骤而有效地抑制革兰氏阳性菌的生长。硫肽的不良药理学性质，特别是它们的低水溶性，阻碍了它们发展为临床有用的抗生素。放线菌提取物文库的抗微生物活性筛选导致发现了来自放线菌属物种UTMC 2475和放线菌属物种UTMC 2448的新型多糖基化硫肽persistathiacin A和B。Persiathiacin A对耐甲氧西林金黄色葡萄球菌（MRSA）和几种结核分枝杆菌菌株（包括耐药和多重耐药临床分离株）具有活性，并且在高达400 μM的浓度下不会显著影响卵巢癌细胞的生长。体外翻译试验表明，与其他硫肽抗生素一样，persathiacin A靶向蛋白质生物合成。多糖基化硫肽是极其罕见的，并且对其生物合成一无所知。测序和分析的放线菌属物种UTMC 2448基因组能够识别推定的persistathiacin生物合成基因簇。由该基因簇编码的细胞色素P450在体外和体内催化那西肽的羟基化，这与该簇指导persistathiacin生物合成的提议一致。该簇中的几个基因编码已知在其他类别的糖基化天然产物的生物合成期间催化脱氧糖的组装和附着的酶的同源物。因此，persathiacins及其生物合成基因簇的发现为开发生物合成工程方法以产生具有增强的药理学性质的新型（多）糖基化硫肽衍生物提供了基础。
Thiopeptides are ribosomally biosynthesized and post-translationally modified peptides (RiPPs) that potently inhibit the growth of Gram-positive bacteria by targeting multiple steps in protein biosynthesis. The poor pharmacological properties of thiopeptides, in particular their low aqueous solubility, has hindered their development into clinically useful antibiotics. Antimicrobial activity screens of a library of Actinobacterial extracts led to discovery of the novel polyglycosylated thiopeptides persiathiacins A and B from Actinokineospora sp. UTMC 2475 and Actinokineospora sp. UTMC 2448. Persiathiacin A is active against methicillin-resistant Staphylococcus aureus (MRSA) and several Mycobacterium tuberculosis strains, including drug-resistant and multidrug-resistant clinical isolates, and does not significantly affect the growth of ovarian cancer cells at concentrations up to 400 μM. In vitro translation assays showed that, like other thiopeptide antibiotics, persiathiacin A targets protein biosynthesis. Polyglycosylated thiopeptides are extremely rare and nothing is known about their biosynthesis. Sequencing and analysis of the Actinokineospora sp. UTMC 2448 genome enabled identification of the putative persiathiacin biosynthetic gene cluster. A cytochrome P450 encoded by this gene cluster catalyses the hydroxylation of nosiheptide in vitro and in vivo, consistent with the proposal that the cluster directs persiathiacin biosynthesis. Several genes in the cluster encode homologues of enzymes known to catalyse the assembly and attachment of deoxysugars during the biosynthesis of other classes of glycosylated natural products. The discovery of the persiathiacins and their biosynthetic gene cluster thus provides the basis for the development of biosynthetic engineering approaches to the creation of novel (poly)glycosylated thiopeptide derivatives with enhanced pharmacological properties.