Photoelectrocyclizations to Virulence Inhibiting Natural Products

光电环化作用抑制天然产物的毒力

基本信息

批准号：
9895835
负责人：
JON Douglas RAINIER
金额：
$ 30.5万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895835
关键词：
Alkenes Amides Antibiotics Bacterial Infections Biological Biological Assay Cell Adhesion Collaborations Communication Core Facility Development Diterpenes Family Goals Gram-Positive Bacteria Growth Indolequinones Innovative Therapy Interruption Lead Methodology Microbial Biofilms Mission Naphthoquinones Natural Products Organic Chemistry Peptidyltransferase Pharmaceutical Chemistry Phase Plant Roots Play Porifera Prevalence Public Health Pyrroloiminoquinones Reaction Reporting Resistance development Role Salvia Structure Testing Torque Toxic effect United States National Institutes of Health Universities Utah Variant Virulence Work analog antimicrobial bacterial resistance chemical synthesis cytotoxicity drug resistant bacteria information gathering inhibitor/antagonist interest novel novel strategies novel therapeutics pressure programs quinone methide scaffold small molecule sortase

项目摘要

The increasing prevalence of drug resistant bacteria has resulted in a dire need for new approaches to antimicrobials. In particular, the discovery and development of small molecules that are not as predisposed to selective pressure and, as a consequence, offer fewer opportunities for the development of resistance, is a topic of current interest and one where we believe we can help to make a difference. This proposal outlines our program is concentrated on developing novel scaffolds aimed at disrupting bacterial communication and virulence, especially in gram-positive bacteria. We propose to study two natural product lead molecules over the course of four phases that combine the development of organic chemistry methodology with total synthesis and SAR. Concurrent to these efforts will be studies whose goals are to ascertain the ability of our synthetic compounds to control virulence. The choice of inhibitors to begin our studies has taken into account the accessibility of the small molecule targets using efficient and novel chemical synthesis methodology, the activity of the targets against virulence targets, including sortase A, and the ability of the compounds to inhibit biofilm formation and to disrupt preformed biofilms. Our lead structures are discorhabdin Z, a pyrroloiminoquinone natural product that comes from the marine sponge, Sceptrella sp. and taxodone, a diterpene natural product of the abietane family that comes from the roots of the sage Salvia austriaca. Both of these agents will synthesized using a unique and stereoselective bis-aryl alkene photochemical electrocyclization reaction sequence. We will continue to develop and optimize the photoelectrocyclization reactions over the course of the proposed efforts. In the third phase of the program we will generate analogs of discorhabdin Z and taxodone aimed at enhancing their virulence activity while tempering, for the discorhabdins, their cytotoxicity. The final phase of the work proposed here will be carried out in collaboration with the University of Utah Medicinal Chemistry Core Facility and will target the development of a panel of assays aimed at gathering information about the antibiotic activity, anti-biofilm activity, sortase A activity, and toxicity of all of our synthetic compounds.

耐药细菌的患病率的增加导致对新方法的迫切需求抗菌剂。特别是，小型发现和发展不易于选择压力的分子，因此提供了阻力发展的机会更少，是当前关注的话题，一个主题我们相信我们可以帮助您有所作为。该建议概述了我们的计划集中于开发旨在破坏细菌交流和的新型脚手架毒力，尤其是革兰氏阳性细菌。我们建议研究两种天然产品在四个阶段的过程中，铅分子结合了有机化学的发展总合成和SAR的方法。这些努力的同时将是研究其目标是要确定我们的合成化合物控制毒力的能力。选择开始研究的抑制剂已经考虑了小分子的可及性使用有效且新颖的化学合成方法的靶标，目标的活性抗毒力靶标，包括分类酶A和化合物的能力抑制生物膜形成并破坏预制的生物膜。我们的铅结构是 Discorhabdin Z，一种来自海洋海绵的吡咯氨基喹酮天然产品 sp。和taxodone，Abietane家族的二萜天然产物，来自鼠尾草salvia austriaca。这两种代理将使用唯一和立体选择性双芳基烯烃光化学电环化反应序列。我们将在整个过程中继续开发和优化光电子环化反应拟议的努力。在程序的第三阶段，我们将生成类似物 Discorhabdin Z和Taxodone旨在增强其回火时的毒力活动对于Discorhabdins，它们的细胞毒性。这里提出的工作的最后阶段将与犹他大学药物化学核心合作进行设施，将针对开发一组旨在收集有关信息的测定面板我们所有的抗生素活性，抗生物胶片活性，排序酶A活性和毒性合成化合物。