Marine sponge depsipeptides to minimize antibiotic collateral damage

海洋海绵缩酚肽可最大程度地减少抗生素的附带损害

• 批准号: 10726689
• 负责人: Alessandra S Eustaquio
• 金额: $ 19.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-19 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726689
• 关键词: Anabolism; Animals; Antibiotic Therapy; Antibiotics; Antidotes; Aromatic Compounds; Bacillus; Bacteria; Crude Extracts; Data; Depsipeptides; Disease; Disease Outcome; Doxycycline; Drug Kinetics; Erythromycin; Family; Future; Growth; Health; Health Personnel; Human; Human Microbiome; Improve Access; Infection; Inflammatory Bowel Diseases; Knock-out; Learning; Length; Libraries; Malignant Neoplasms; Mental disorders; Methods; Microbe; Names; Natural Products; Nature; Neurodegenerative Disorders; Oral; Outcome; Outpatients; Pharmaceutical Preparations; Pharmacologic Substance; Porifera; Predisposition; Reporting; Role; Series; Side; Testing; Therapeutic; Toxic effect; Translating; United States; clinically relevant; commensal bacteria; dysbiosis; gut microbiota; human pathogen; insight; large scale production; marine; microbiome; mutant; pathogen; pathogenic bacteria; peptide natural products; prevent; screening; water solubility

Project Summary In 2020 alone, about 200 million oral antibiotic prescriptions were dispensed by outpatient healthcare providers in the United States. Broad-spectrum antibiotics make up most of these prescriptions. However, in addition to targeting the intended pathogen, broad-spectrum antibiotics alter the composition of the human microbiome (dysbiosis). Dysbiosis caused by broad-spectrum antibiotic treatment can increase susceptibility to or worsen the outcome of disease, including inflammatory bowel disease, cancer, and psychiatric and neurodegenerative disorders. Therefore, it is important to develop therapeutic strategies that minimize the collateral damage of broad-spectrum antibiotics. Here we propose to explore molecules that selectively antagonize the activity of broad-spectrum antibiotics as a strategy to minimize dysbiosis. The advantage of selective antidotes over the alternative strategy of developing narrow-spectrum or pathogen-targeted antibiotics is to be able to continue to use already developed broad-spectrum antibiotics. Proof-of-concept for the selective antidote strategy has been recently provided. From the four previously identified antidotes, three are not available in the US due to their toxicity, and the remaining one has poor water solubility and unfavorable pharmacokinetics. We have recently discovered a family of depsipeptide natural products we named pseudovibriamides. Pseudovibriamides are produced by Pseudovibrio bacteria that are part of the healthy microbiome of marine sponges. Interestingly, Pseudovibrio has been proposed to contribute to marine sponge health by producing broad-spectrum antibiotics that can prevent the growth of pathogens. Marine sponges are ancient animals that form important symbiotic relationships with their microbes. Thus, broad-spectrum antibiotics known to be produced by Pseudovibrio and other sponge bacteria would cause dysbiosis in the sponge animal. We hypothesize that pseudovibriamides act as selective antidotes to protect commensal bacteria and the sponge host but allow activity against pathogens. We envisage the ecological role of pseudovibriamides may be translated into pharmaceutical applications. This proposal has two aims. Aim 1 is to improve access to pseudovibriamides using biosynthetic methods and Aim 2 is to explore their antibiotic and strain spectra. We will use sponge bacteria commensals and pathogens as controls to test the hypothesis. We will then explore the spectrum of antidote activity of pseudovibriamides with widely used antibiotics and the human pathogens they are intended to treat, and with prevalent and abundant human commensals. Thus, this proposal will enable facile access to and will explore the antidote spectrum of a family of bacterial natural products shown to have antibiotic antidote activity. What we learn will serve as steppingstones for future studies on their mode of action to enable the discovery of further antidotes.

项目摘要 仅在2020年，门诊医疗服务提供者就开出了约2亿份口服抗生素处方 在美国广谱抗生素构成了这些处方的大部分。不过除了 广谱抗生素针对预期的病原体，改变了人体微生物组的组成 （生态失调）。由广谱抗生素治疗引起的生态失调可增加易感性或恶化 疾病的结果，包括炎症性肠病、癌症、精神病和神经退行性疾病 紊乱因此，重要的是开发治疗策略，最大限度地减少并发症的损害。 广谱抗生素在这里，我们建议探索分子，选择性拮抗的活动， 广谱抗生素作为减少生态失调的策略。选择性解毒剂的优势在于 开发窄谱或病原体靶向抗生素的替代策略是能够继续 使用已经开发的广谱抗生素。选择性解毒剂策略的概念验证已经 最近提供的。在先前确定的四种解毒剂中，有三种由于其 毒性，而剩余的一种具有差的水溶性和不利的药代动力学。我们最近 发现了一个缩肽天然产物家族，我们将其命名为假弧菌酰胺。假弧菌酰胺类是 由假弧菌属细菌产生，假弧菌属细菌是海绵健康微生物组的一部分。有趣的是， 假弧菌已被提出通过产生广谱抗生素来促进海绵健康 可以防止病原体的生长。海洋海绵是古老的动物， 与微生物的关系。因此，已知由假弧菌属产生的广谱抗生素和 其它海绵细菌会导致海绵动物的生态失调。我们假设假弧菌酰胺类 作为选择性解毒剂，以保护海绵细菌和海绵宿主，但允许对病原体的活性。 我们设想假弧菌酰胺的生态作用可以转化为药物应用。这 建议有两个目的。目标1是使用生物合成方法改善获得假弧菌酰胺的途径， 是探索它们的抗生素和菌株谱。我们将使用海绵细菌和病原体作为 控制来检验假设。然后，我们将探索假弧菌酰胺类的解毒剂活性谱， 广泛使用的抗生素和它们旨在治疗的人类病原体， 人体骨骼因此，这项建议将使人们能够容易地获得并探索一种 细菌天然产物家族，具有抗生素解毒活性。我们学到的东西 为今后研究其作用方式，以发现更多的解毒剂奠定了基础。