Bioprospecting antibiotics in the fungal secondary metabolome

真菌次级代谢组中抗生素的生物勘探

• 批准号: 8582783
• 负责人: BILL J BAKER
• 金额: $ 17.16万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582783
• 关键词: Address; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Biological Assay; Biological Factors; Cessation of life; Chemical Agents; Chemicals; Chemistry; Collaborations; Communicable Diseases; Communities; Community Hospitals; Complex; Coupled; Data; Development; Disease; Drug resistance; Epigenetic Process; Eukaryotic Cell; Evaluation; Florida; Future; Growth; Infection; Investigation; Laboratories; Lead; Libraries; Life; Marines; Metabolic Pathway; Methods; Microbial Biofilms; Microbiology; Mining; Multi-Drug Resistance; Nature; Nosocomial Infections; Organism; Pathway interactions; Penicillins; Play; Poison; Production; Property; Public Health; Role; Streptomycin; Structure; Testing; Therapeutic; Time; Toxic effect; Trust; Vancomycin; Work; World Health Organization; analog; antimicrobial drug; antineoplastic antibiotics; bacterial resistance; base; cytotoxic; drug discovery; drug resistant bacteria; endophytic fungi; experience; fighting; fungus; innovation; liquid chromatography mass spectrometry; microorganism; mortality; novel; novel strategies; novel therapeutics; pathogen; public health relevance; scaffold; screening; small molecule; success; tool

DESCRIPTION (provided by applicant): Despite the notable success of antibiotics, bacterial diseases remain the second-leading cause of mortality worldwide, causing 17 million deaths globally. One of the most significant public health concerns in the context of infectious disease is the continued and rapid emergence of drug resistant bacteria during antibiotic treatment. As such, there is an undeniable and desperate need to develop new antibacterial therapeutics to fight multi-drug resistant infections. Indeed, the pace of drug resistance has outstripped the discovery of new antimicrobial agents, creating an urgent need for new antibiotics with novel mechanisms of action. Natural products have played a major role in antibiotic chemotherapy, beginning with penicillin in 1941, and followed by a litany of other trusted agents over the ensuing decades. In the last twenty-five years alone, natural products have inspired more than 75% of small molecule antibiotics, and two of only three new antibiotic classes approved in the last forty years. A major concern, however, is that natural product based divining for new lead agents is becoming increasingly difficult. This is largely believed to result from the comprehensive mining of available producing organisms, and a relatively complete understanding of their metabolic pathways. However, it is also widely projected that the wealth and availability of compounds produced by environmental microorganisms has actually been sorely underestimated, in large part because many biosynthetic pathways are silent under laboratory growth conditions. In this study, we propose to take the novel, but precedented, approach of epigenetically modifying a unique library of marine-margin endophytic fungi to trigger production of latent and cryptic metabolites. These organisms are ideal for use in such a project as they are almost entirely untapped in the context of antibacterial drug discovery, whilst at the same time possessing inherently complex secondary metabolomes. As such, we seek to unlock dormant metabolic pathways in our fungal isolates via epigenetic manipulation, for the exploitation of new secondary metabolites that possess antibacterial activity. This will be achieved by: 1. The production, purification and structural analysis of natural product lead compounds. This aim will provide chemodiversity for screening, derived from endophytic fungi cultivated both with and without epigenetic modifiers. Antibacterial extracts derived from these cultures will be isolated, purified and their structures determined. Novel chemotypes retaining favorable bioactivity will then further characterized by: 2. A comprehensive activity and toxicity profiling of lead agents. In this aim we will perform a prioritized and rationalized analysis of led agents by determining their antibacterial spectrum of activity against multi-drug resistant ESKAPE pathogens, their cytotoxic effects towards eukaryotic cells, their anti-biofilm properties, and the potential for bacterial resistance to their effects. We contend that our preliminary work; coupled with novel approaches, give our project a very high chance of yielding new and novel chemical scaffolds for future antibiotic development.

描述（由申请人提供）：尽管抗生素取得了显著的成功，但细菌性疾病仍然是全球第二大死亡原因，导致全球1700万人死亡。在感染性疾病的背景下，最重要的公共卫生问题之一是抗生素治疗期间耐药细菌的持续和快速出现。因此，不可否认的是，迫切需要开发新的抗菌治疗剂来对抗多重耐药感染。事实上，耐药性的发展速度已经超过了新抗菌药物的发现，迫切需要具有新作用机制的新抗生素。天然产物在抗生素化疗中发挥了重要作用，从1941年的青霉素开始，在随后的几十年里，其他一系列值得信赖的药物也相继问世。仅在过去的25年里，天然产物就激发了超过75%的小分子抗生素，并且在过去的40年里，只有三种新的抗生素类别被批准。然而，一个主要的问题是，基于天然产物的新的主要代理人的占卜变得越来越困难。这在很大程度上被认为是由于对现有生产生物的全面挖掘，以及对其代谢途径的相对完整的理解。然而，人们也普遍认为，环境微生物产生的化合物的丰富性和可用性实际上被严重低估了，这在很大程度上是因为许多生物合成途径在实验室生长条件下是沉默的。在这项研究中，我们建议采取新颖的，但有先例的，表观遗传修饰的海洋边缘内生真菌的独特库，以触发生产的潜在和隐蔽的代谢产物的方法。这些生物体非常适合用于这样的项目，因为它们在抗菌药物发现的背景下几乎完全未被开发， 同时具有内在复杂的次级代谢组。因此，我们寻求通过表观遗传操作解锁真菌分离物中的休眠代谢途径，以开发具有抗菌活性的新次级代谢产物。这将通过以下方式实现：1.天然产物先导化合物的制备、纯化及结构分析。这一目标将提供筛选的化学多样性，来自内生真菌培养和表观遗传修饰剂。从这些培养物中提取的抗菌提取物将被分离、纯化并确定其结构。保留有利生物活性的新化学型将进一步表征为：2.一个全面的活性和毒性分析的铅剂。在这一目标中，我们将通过确定其对多药耐药ESKAPE病原体的抗菌活性谱、其对真核细胞的细胞毒性作用、其抗生物膜特性以及细菌对其作用的耐药性来对主导药物进行优先化和合理化分析。我们认为，我们的初步工作，加上新的方法，给我们的项目产生新的和新颖的化学支架为未来的抗生素开发的机会很高。