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物衍生抗生素证明， 迫切需要独特的方法来获得新的抗菌支架和活性。然而，最近激增的 在对微生物基因组的仔细研究中提供的证据表明，大量的化学支架隐藏在 在新生的生物合成途径（BSP）仍然未被发现。捕食性粘细菌 超过600种不同的天然产物进入微生物化学空间，包括42种新的支架，其中29种表现出 抗菌或抗真菌活性。粘细菌是大量未开发的 大细菌基因组的化学空间充满了BSP，通常占其总量的10 基因组含量然而，与从其他生物体（如植物或海洋生物）分离的天然产物不同， 海绵直接从竞争环境中隔离，细菌提取物从自然环境中， 海洋和陆地通常会忽略低于当前检测水平的化学实体。相反，细菌天然 产品主要是从从群落中移除的生产物种的无菌培养中分离出来的 维护和竞争。我们假设，诱导捕食的粘细菌培养条件 或者通过补充来自被捕食细菌的分离的胞外多糖（EPS），或者通过补充非纯性的、共 利用已知采石场进行种植将产生抗菌新化学实体（NCEs）。我们将 分子网络质谱数据集收集的12个粘细菌的培养，使用这些 全球天然产物社交分子网络（GNPS）开放获取平台 以有效鉴定所产生的NCE，用于进一步的抗菌评估。这些分子网络的努力将 生成1，008个数据集，这些数据集将代表粘细菌暴露于猎物时可用的化学空间 或孤立的猎物EPS，并显着有利于去复制和发现的努力。我们保守的预期 每种被调查的粘细菌捕食者1-2个NCE将提供总共13-26个潜在的抗菌NCE 在完成拟议的研究。

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.