Zvanych Rostyslav, Lukenda Nikola, Li Xiang, Kim Janice J, Tharmarajah Satheeisha, Magarvey Nathan A
Department Chemistry & Chemical Biology, McMaster University, M.G. DeGroote Institute for Infectious Disease Research, 1200 Main St. W, Hamilton, Ontario L8N 3Z5, Canada.
Mol Biosyst. 2015 Jan;11(1):97-104. doi: 10.1039/c4mb00406j. Epub 2014 Sep 11.
Streptococcus mutans, a Gram-positive human commensal and pathogen, is commonly recognized as a primary causative agent in dental caries. Metabolic activity of this strain results in the creation of acids and secreted products are recognized as pathogenic factors and agents that promote immunomodulation by stimulating the release of pro-inflammatory cytokines. Products of secondary metabolic pathways of microorganisms from the human microbiome are increasingly investigated for their immunomodulatory functions. In this study, we sought to explore the metabolomic output of nonribosomal peptide pathways within the model S. mutans strain, S. mutans UA159, using a systems metabolomic approach to gain in-depth analysis on products created by this organism and probe these molecules for their immunomodulatory function. Comparative metabolomics and biosynthetic studies using wild-type and nonribosomal peptide deletion strains (within the mutanobactin biosynthetic locus), precursor feedings (fatty acid derivatives) led to the identification of 58 metabolites, 13 of which were structurally elucidated. In addition to these, an assembly line derailment product, mutanamide, was also identified and used to assess immunomodulatory properties of mutanobactins and actions relating to their previously reported functions describing hyphal inhibitory profiles in Candida albicans. The results of this study demonstrate both the complexity and the divergent roles of products stemming from this unique biosynthetic assembly line.
变形链球菌是一种革兰氏阳性人体共生菌和病原体，通常被认为是龋齿的主要致病因素。该菌株的代谢活动会产生酸，其分泌产物被认为是致病因素以及通过刺激促炎细胞因子释放来促进免疫调节的因子。来自人类微生物组的微生物次生代谢途径的产物因其免疫调节功能而受到越来越多的研究。在本研究中，我们试图利用系统代谢组学方法探索变形链球菌模式菌株变形链球菌UA159中非核糖体肽途径的代谢组输出，以深入分析该生物体产生的产物，并探究这些分子的免疫调节功能。使用野生型和非核糖体肽缺失菌株（在变链菌素生物合成位点内）进行比较代谢组学和生物合成研究、前体喂养（脂肪酸衍生物），从而鉴定出58种代谢物，其中13种的结构得到了阐明。除此之外，还鉴定出了一种装配线脱轨产物变链酰胺，并用于评估变链菌素的免疫调节特性以及与其先前报道的描述白色念珠菌菌丝抑制谱的功能相关的作用。本研究结果证明了源自这一独特生物合成装配线的产物的复杂性和不同作用。
