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

响应不同的 LPS 多糖结构调节粘细菌外膜囊泡的抗菌含量。

基本信息

批准号：
10165749
负责人：
David Cole Stevens
金额：
$ 25.35万
依托单位：
UNIVERSITY OF MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10165749
关键词：
Address Anti-Bacterial Agents Antibiotics Antifungal Agents Antineoplastic Agents Attention Autolysin Bacteria Bacterial Genome Biological Biological Assay Centers of Research Excellence Chemicals Clinical Communities Culture Media Data Set Deltastab Detection Drug Delivery Systems Endopeptidases Environment Enzymes Escherichia coli Exhibits Exposure to Genome Genomics Global Change Glycoside Hydrolases Growth Investigation Lipopolysaccharides LytA enzyme Maintenance Mass Spectrum Analysis Membrane Metabolic Methods Microbe Microbial Biofilms Molecular Myxococcales Myxococcus xanthus Natural Products O Antigens Organism Pathogenicity Pathway interactions Plants Polysaccharides Porifera Predatory Behavior Production Pseudomonas aeruginosa Reporting Research Soil Source Structure Supplementation Therapeutic Vaccines Vesicle amidase antimicrobial comparative expectation microbial microbial genome natural antimicrobial novel pathogen programs response scaffold small molecule social

项目摘要

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.

项目概要 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表明迫切需要独特的方法来获得新的抗菌支架和活性。然而最近的飙升对微生物基因组的审查提供的证据表明，隐藏着大量的化学支架新生的生物合成途径（BSP）中的某些成分仍未被发现。捕食性粘细菌做出了贡献超过 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 种展示仅过去 6 年的抗菌或抗真菌活性。粘细菌体现了丰富的未开发资源具有大型细菌基因组的化学空间充满 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来的天然产物不同，直接从竞争性环境中分离出来的海绵，从自然环境中提取的细菌提取物海洋和陆地经常遗漏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通过补充来自猎物细菌的分离的胞外多糖（EPS）或非无菌的共- 与已知采石场一起种植将产生抗菌新化学实体（NCE）。我们将使用这些从 12 种粘细菌培养中收集的分子网络质谱数据集全球天然产品社交分子网络 (GNPS) 开放获取平台促进的条件有效识别由此产生的 NCE，以进行进一步的抗菌评估。这些分子网络工作将生成 1,008 个数据集，这些数据集代表粘细菌在接触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工作。我们的保守预期每个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 完成拟议的研究后。