Modulation of the antimicrobial content of myxobacteria outer membrane vesicles in response to varying LPS polysaccharide structures.

项目摘要 30年来没有一种新发现的临床批准的天然产品衍生抗生素表明 迫切需要独特的方法来获得新的抗菌支架和活动。然而，最近的涨势 对微生物基因组的仔细研究提供了证据表明，大量的化学支架隐藏在 在新生的生物合成途径(BSP)仍未被发现。捕食性粘性细菌对 超过600种不同的天然产物进入微生物化学领域，包括42种新型支架，其中29种展示了 仅在过去6年中就有抗菌或抗真菌活动。粘性细菌是未开发的丰富的 含有大量细菌基因组的化学空间，这些基因组充满了BSP，通常占其总数的10% 基因组内容。然而，与从植物或海洋等其他生物中分离出的天然产品不同 海绵直接从竞争环境中隔离，细菌提取物从自然环境中 海洋和陆地常常忽略低于当前检测水平的化学物质。相反，细菌是天然的 产品主要是从从群落中移走的生产物种的无菌栽培中分离出来的 维护和竞争。我们假设引起捕食的粘液细菌培养条件 无论是通过补充从猎物细菌中分离的胞外多糖(EPS)，还是通过非无菌，共培养 与已知采石场的种植将导致产生抗微生物的新化学实体(NCEs)。我们会 从12个粘性细菌的培养中收集的分子网络质谱学数据集 全球天然产品社会分子网络(GNPS)开放获取平台提供便利的条件 以有效地确定所产生的NCEs，以供进一步的抗菌素评估。这些分子网络的努力将 生成1,008个数据集，这些数据集将表示粘细菌在接触猎物时可用的化学空间 或孤立的猎物EPS，并极大地有利于去复制和发现努力。我们保守的期望 每只被调查的粘杆菌捕食者1-2个NCEs将提供总共13-26个潜在的抗微生物NCEs 在完成拟议的研究后。

Project Summary The 30-year absence of a newly discovered clinically approved natural product-derived antibiotic demonstrates the dire need for unique methods to access new antimicrobial scaffolds and activities. However, the recent surge in scrutiny of microbial genomes provides evidence to indicate that an abundance of chemical scaffolds hidden within nascent biosynthetic pathways (BSPs) remain undiscovered. Predatory myxobacteria have contributed over 600 distinct natural products to the microbial chemical space including 42 novel scaffolds of which 29 exhibit antibacterial or antifungal activities in the last 6 years alone. Myxobacteria exemplify the abundance of untapped chemical space with large bacterial genomes replete with BSPs that typically account for 10% of their total genomic content. However, unlike natural product isolations from other organisms such as plants or marine sponges sequestered directly from competitive surroundings, bacterial extracts from natural environments both marine and terrestrial often omit chemical entities below current detection levels. Instead, bacterial natural products are predominately isolated from axenic cultivation of a producing species removed from community maintenance and competition. We hypothesize that myxobacterial cultivation conditions that induce predation either through supplementation with isolated exopolysaccharide (EPS) from prey bacteria or non-axenic, co- cultivation with known quarry will result in production of antimicrobial new chemical entities (NCEs). We will molecular network mass spectrometry datasets collected from the cultivation of 12 myxobacteria using these conditions facilitated by the Global Natural Products Social Molecular Networking (GNPS) open access platform to efficiently identify resulting NCEs for further antimicrobial assessment. These molecular networking efforts will generate 1,008 datasets that will represent the chemical space available to myxobacteria when exposed to prey or isolated prey EPS and significantly benefit dereplication and discovery efforts. Our conservative expectation of 1-2 NCEs per investigated myxobacterial predator would provide a total of 13-26 potential antimicrobial NCEs upon completion of the proposed research.