Isoindolinones as Antimicrobial Agents

作为抗菌剂的异吲哚啉酮

• 批准号: 7483514
• 负责人: Nigel D PRIESTLEY
• 金额: $ 22.56万
• 依托单位: PROMILIAD BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483514
• 关键词: Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacillus subtilis; Bacteria; Bacterial Infections; Biological Assay; Chemistry; Class; Communicable Diseases; Coupling; Cyclization; DNA; DNA Sequence Rearrangement; Development; Diels Alder reaction; Diversity Library; Feasibility Studies; Goals; Lactams; Lead; Libraries; Measures; Methods; Nitrogen; Oxygen; Pattern; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Predisposition; Preparation; Proteins; Public Health; Rate; Relative (related person); Research; Resistance; Screening procedure; Series; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Staphylococcus aureus; Testing; Work; analog; antimicrobial; antimicrobial drug; bacterial resistance; member; mutant; novel; pathogen; prototype

DESCRIPTION (provided by applicant): Antibiotic resistance among common pathogens is a serious public health problem because it compromises our ability to treat many infectious diseases. The problem has been compounded by the lack of discovery of new antibiotics that act in novel ways. Such compounds are critically needed as bacterial resistance to older antibiotics, and even their newer derivatives, is growing. The goal of our work is to develop a new set of antibacterial compounds that we have discovered, the isoindolinone derivative, as agents that are active against Gram-positive pathogens. In this Phase I SBIR feasibility study we ask a simple question: Can we demonstrate that our novel isoindolinone compounds have a good potential to lead to a new antibacterial drug? We will determine the general mechanism of action of our current lead compound. We will also prepare additional analogs to identify the general structural activity relationship of our isoindolinone derivatives. Our studies will show if we are able to prepare selective and druggable compounds suitable for further development in a Phase II study. Specifically, we plan to determine the mechanism of action of the isoindolinone class by determining if our lead compound perturbs the synthesis rates of protein, RNA, and DNA. We will also assess the ability of our lead compound to induce resistance and determine the synergy and antagonism of our lead compound with antibiotics of known mechanism of action. We will also prepare a highly focused set of analogs of our lead compound, in order to determine an optimal substitution pattern around a key aromatic ring. PUBLIC HEALTH RELEVANCE: The ability to treat bacterial infections has become compromised by a growing resistance among common bacteria to antibiotics; this has become a significant public health problem. We have identified a novel structural class of antibacterial agents, and will study the mechanism of action and prepare a select set of analogs to evaluate for antibacterial activity. If successful, this project will provide a new class of antibacterial agents to combat the problem of antibiotic resistance.

描述（由申请人提供）：常见病原体中的抗生素耐药性是一个严重的公共卫生问题，因为它损害了我们治疗许多传染病的能力。由于缺乏以新颖方式起作用的新抗生素的发现，这个问题加剧了问题。这样的化合物非常需要，因为细菌对旧抗生素的耐药性，甚至其较新的衍生物也在增长。我们工作的目的是开发我们发现的一组新的抗菌化合物，即异丁氏素衍生物，作为对革兰氏阳性病原体有效的药物。在这一阶段，我们提出了一个简单的问题：我们可以证明我们的新型异丁氏素化合物具有导致新抗菌药物的良好潜力吗？我们将确定当前铅化合物的一般作用机理。我们还将准备其他类似物，以确定异源酮衍生物的一般结构活动关系。我们的研究将表明我们是否能够在II期研究中准备适合进一步开发的选择性和可毒品。具体而言，我们计划通过确定我们的铅化合物是否伴随蛋白质，RNA和DNA的合成速率来确定异丁氏素类别的作用机理。我们还将评估铅化合物诱导抗性的能力，并通过已知的作用机理的抗生素确定铅化合物的协同和拮抗作用。我们还将准备一组高度集中的铅化合物类似物，以确定围绕关键芳族环的最佳替代模式。公共卫生相关性：治疗细菌感染的能力已被普通细菌对抗生素的抗药性日益增强所损害。这已成为一个重大的公共卫生问题。我们已经确定了一种新型的抗菌剂结构类别，并将研究作用机理，并准备一组类似物来评估抗菌活性。如果成功的话，该项目将提供一类新的抗菌剂，以应对抗生素耐药性问题。