Marine sponge depsipeptides to minimize antibiotic collateral damage

项目摘要 仅在2020年，门诊医疗保健提供者就开出了约2亿张口服抗生素处方 在美国。广谱抗生素构成了这些处方的大部分。然而，除了 针对预期的病原体，广谱抗生素改变了人类微生物组的组成。 (生态失调)。广谱抗生素治疗引起的微生物失调会增加易感性或恶化 疾病的结果，包括炎症性肠病、癌症、精神病和神经退行性变 精神错乱。因此，重要的是制定治疗策略，将附带损害降至最低。 广谱抗生素。在这里，我们建议探索选择性拮抗血管紧张素转换酶活性的分子 广谱抗生素作为一种最大限度减少生物失调的策略。选择性解毒剂的优势 开发窄谱或针对病原体的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被 最近提供的。在之前确定的四种解毒剂中，有三种在美国无法获得，原因是 毒性，其余一种水溶性较差，不利于药代动力学。我们最近做了 发现了一类脱脂肽类天然产物，我们将其命名为假弧菌胺。假弧菌属 产生的假弧菌是海洋海绵健康微生物群的一部分。有趣的是， 假弧菌被认为可以通过产生广谱抗生素来促进海绵的健康。 这可以防止病原体的生长。海绵是形成重要共生关系的古老动物。 与它们的微生物之间的关系。因此，已知的由假弧菌和假弧菌产生的广谱抗生素 其他海绵细菌会导致海绵动物的生态失调。我们假设假性弧菌的作用是 作为选择性解毒剂，保护共生菌和海绵宿主，但允许对抗病原体。 我们预计，假性弧菌的生态作用可能会转化为药物应用。这 提案有两个目的。目标1是使用生物合成方法改善获得假性弧菌胺的途径，目标2 是探索他们的抗生素和菌株谱。我们将使用海绵细菌共生体和病原体作为 对照来检验这一假设。然后，我们将探索伪弧菌胺的解毒活性谱 广泛使用的抗生素及其意在治疗的人类病原体，并具有普遍和丰富的 人类的共生关系。因此，这项提案将使人们能够方便地访问并探索一种 具有抗生素解毒剂活性的细菌天然产物家族。我们所学到的将会成为 为未来研究它们的作用模式提供了垫脚石，从而能够发现更多的解毒剂。

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.