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着的成功，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。传染病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快速出现。因此，不可否认且迫切需要开发新的抗菌疗法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速度，因此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，在接下来的几十年里出现了一系列其他值得信赖的药物。仅在过去 25 年中，天然产物就启发了超过 75% 的小分子抗生素，以及过去 40 年来批准的三种新抗生素类别中的两种。然而，一个主要问题是，基于天然产物的新主导药物的预测变得越来越困难。这在很大程度上被认为是由于对现有生产生物体的全面挖掘，以及对其代谢途径的相对完整的了解。然而，人们普遍认为，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，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，我们建议采用新颖但有先例的方法，对独特的海洋边缘内生真菌库进行表观遗传修饰，以触发潜在和神秘代谢物的产生。这些生物体非常适合在此类项目中使用，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 同时拥有固有的复杂的次级代谢组。因此，我们寻求通过表观遗传操作来解锁真菌分离株中的休眠代谢途径，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生产、纯化和结构分析。这一目标将为筛选提供来自使用和不使用表观遗传修饰剂培养的内生真菌的化学多样性。来自这些培养物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： 2.先导药物的综合活性和毒性分析。为此，我们将通过确定主导药物对多重耐药 ESKAPE 病原体的抗菌活性谱、它们对真核细胞的细胞毒性作用、它们的抗生物膜特性以及​​细菌对其耐药的潜力，对主导药物进行优先和合理化的分析。影响。我们认为我们的初步工作；加上新颖的方法，使我们的项目有很大机会为未来的抗生素开发产生新型化学支架。