Castiglione Franca, Cavaletti Linda, Losi Daniele, Lazzarini Ameriga, Carrano Lucia, Feroggio Marina, Ciciliato Ismaela, Corti Emiliana, Candiani Gianpaolo, Marinelli Flavia, Selva Enrico
Vicuron Pharmaceuticals, Via R. Lepetit 34, 21040 Gerenzano, (VA) Italy.
Biochemistry. 2007 May 22;46(20):5884-95. doi: 10.1021/bi700131x. Epub 2007 May 1.
Important classes of antibiotics acting on bacterial cell wall biosynthesis, such as beta-lactams and glycopeptides, are used extensively in therapy and are now faced with a challenge because of the progressive spread of resistant pathogens. A discovery program was devised to target novel peptidoglycan biosynthesis inhibitors capable of overcoming these resistance mechanisms. The microbial products were first screened according to their differential activity against Staphylococcus aureus and its L-form. Then, activities insensitive to the addition of a beta-lactamase cocktail or d-alanyl-d-alanine affinity resin were selected. Thirty-five lantibiotics were identified from a library of broth extracts produced by 40,000 uncommon actinomycetes. Five of them showed structural characteristics that did not match with any known microbial metabolite. In this study, we report on the production, structure determination, and biological activity of one of these novel lantibiotics, namely, planosporicin, which is produced by the uncommon actinomycete Planomonospora sp. Planosporicin is a 2194 Da polypeptide originating from 24 proteinogenic amino acids. It contains lanthionine and methyllanthionine amino acids generating five intramolecular thioether bridges. Planosporicin selectively blocks peptidoglycan biosynthesis and causes accumulation of UDP-linked peptidoglycan precursors in growing bacterial cells. On the basis of its mode of action and globular structure, planosporicin can be assigned to the mersacidin (20 amino acids, 1825 Da) and the actagardine (19 amino acids, 1890 Da) subgroup of type B lantibiotics. Considering its spectrum of activity against Gram-positive pathogens of medical importance, including multi-resistant clinical isolates, and its efficacy in vivo, planosporicin represents a potentially new antibiotic to treat emerging pathogens.
作用于细菌细胞壁生物合成的重要抗生素类别，如β-内酰胺类和糖肽类，在治疗中被广泛使用，而如今由于耐药病原体的不断传播，它们面临着挑战。为此设计了一个发现计划，旨在寻找能够克服这些耐药机制的新型肽聚糖生物合成抑制剂。首先根据微生物产物对金黄色葡萄球菌及其L型的差异活性进行筛选。然后，选择对添加β-内酰胺酶混合物或D-丙氨酰-D-丙氨酸亲和树脂不敏感的活性物质。从40000株罕见放线菌产生的发酵液提取物文库中鉴定出35种羊毛硫抗生素。其中5种显示出与任何已知微生物代谢产物都不匹配的结构特征。在本研究中，我们报告了其中一种新型羊毛硫抗生素——扁平孢菌素的产生、结构测定及生物活性，它由罕见放线菌扁平孢单胞菌属产生。扁平孢菌素是一种由24种蛋白质氨基酸组成的2194 Da多肽。它含有丙氨酸硫醚氨酸和甲基丙氨酸硫醚氨酸氨基酸，形成了5个分子内硫醚桥。扁平孢菌素选择性地阻断肽聚糖生物合成，并导致生长中的细菌细胞中UDP连接的肽聚糖前体积累。基于其作用方式和球状结构，扁平孢菌素可归为B型羊毛硫抗生素中的梅萨杀菌素（20个氨基酸，1825 Da）和阿塔加丁（19个氨基酸，1890 Da）亚组。考虑到其对包括多重耐药临床分离株在内的具有医学重要性的革兰氏阳性病原体的活性谱及其体内疗效，扁平孢菌素代表了一种治疗新出现病原体的潜在新型抗生素。
