Roseocin, a Novel Two-Component Lantibiotic from an Actinomycete. Mangal et al

Lantibiotics are lanthionine ring containing natural products that belong to the class of ribosomally synthesized and post-translationally 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. Post-translationally modified lanthipeptides of this cluster were obtained by heterologous expression of the genes in E. 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 disulphide 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.羊毛硫抗生素（lantibiotics）是一类含有羊毛硫氨酸环的天然产物，隶属于核糖体合成且翻译后修饰肽（RiPPs）家族。近年来，微生物基因组数据的可及性不断提升与计算机模拟分析工具（in silico analysis tools）的日益丰富，极大加速了这类极具潜力的抗生素替代物的发现进程。依托基因组挖掘策略，研究人员在放线菌玫瑰孢链霉菌（Streptomyces roseosporus NRRL 11379）的基因组中，鉴定出了一条编码推定双组分羊毛硫抗生素玫瑰霉素（roseocin）的生物合成基因簇。通过在大肠杆菌（E. coli）中对该基因簇内的相关基因进行异源表达，成功获得了经翻译后修饰的羊毛硫肽；随后借助GluC内切蛋白酶、蛋白酶K等商用蛋白酶，将其体外重构为具有生物活性的成熟形式。这两条肽链对革兰氏阳性菌展现出协同抗菌活性，其中包括世界卫生组织（WHO）优先关注的耐药病原体耐甲氧西林金黄色葡萄球菌（MRSA）与耐万古霉素肠球菌（VRE）。结构表征结果证实，单一多功能羊毛硫氨酸合成酶RosM可介导该体系的翻译后修饰：在α肽链中形成带有不可或缺二硫键的4个（甲基）羊毛硫氨酸环，在β肽链中则形成6个（甲基）羊毛硫氨酸环。玫瑰霉素是首个源自非厚壁菌门、具备广泛羊毛硫氨酸交联结构的双组分羊毛硫抗生素。