Department of Biochemistry, Basic Medical Sciences Block-II, Panjab University, Chandigarh, India.
Mol Microbiol. 2020 Feb;113(2):326-337. doi: 10.1111/mmi.14419. Epub 2019 Nov 27.
Lantibiotics are lanthionine ring containing natural products that belong to the class of ribosomally synthesized and posttranslationally modified peptides (RiPPs). Recent expansion in the availability of microbial genome data and in silico analysis tools have accelerated the discovery of these promising alternatives to antibiotics. Following the genome-mining approach, a biosynthetic gene cluster for a putative two-component lantibiotic, roseocin, was identified in the genome of an Actinomycete, Streptomyces roseosporus NRRL 11379. Posttranslationally modified lanthipeptides of this cluster were obtained by heterologous expression of the genes in Escherichia coli, and were in vitro reconstituted to their bioactive form by exploiting commercial proteases like endoproteinase GluC, and proteinase K. The two peptides displayed synergistic antimicrobial activity against Gram-positive bacteria including the WHO high-priority pathogens, MRSA and VRE. Structural characterization confirmed the installation of four (methyl)lanthionine rings with an indispensable disulfide bond in the α-peptide, and six (methyl)lanthionine rings in the β-peptide, by a single promiscuous lanthionine synthetase, RosM. Roseocin is the first two-component lantibiotic from a non-Firmicute, with extensive lanthionine bridging.
类杆菌素是一种含有[l]{.smallcaps}-高丝氨酸内酯环的天然产物，属于核糖体合成和翻译后修饰肽（RiPPs）的范畴。最近，随着微生物基因组数据的可用性和计算机分析工具的发展，这些有前途的抗生素替代品的发现速度大大加快。采用基因组挖掘方法，从放线菌链霉菌玫瑰孢变种 NRRL 11379 的基因组中鉴定出了一个假定的双组分类杆菌素 roseocin 的生物合成基因簇。通过在大肠杆菌中异源表达基因，获得了该基因簇中经翻译后修饰的类杆菌素，然后利用内切蛋白酶 GluC 和蛋白酶 K 等商业蛋白酶将其体外复性为具有生物活性的形式。这两种肽对革兰氏阳性菌（包括世界卫生组织高优先级病原体耐甲氧西林金黄色葡萄球菌和万古霉素耐药肠球菌）表现出协同抗菌活性。结构特征证实，由单个混杂的[l]{.smallcaps}-高丝氨酸内酯合成酶 RosM 在 α-肽中安装了四个（甲基）[l]{.smallcaps}-高丝氨酸内酯环和一个不可或缺的二硫键，在 β-肽中安装了六个（甲基）[l]{.smallcaps}-高丝氨酸内酯环。Roseocin 是第一个来自非Firmicutes 的双组分类杆菌素，具有广泛的[l]{.smallcaps}-高丝氨酸内酯桥。
