Isoindolinones as Antimicrobial Agents

描述（由申请人提供）：常见病原体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。由于缺乏以新方式发挥作用的新抗生素，这个问题变得更加复杂。由于细菌对旧抗生素甚至其新衍生物的耐药性正在增长，因此迫切需要此类化合物。我们工作的目标是开发一套新的抗菌化合物，我们已经发现，异吲哚啉酮衍生物，作为代理商，是积极的革兰氏阳性病原体。在这项I期SBIR可行性研究中，我们提出了一个简单的问题：我们能否证明我们的新型异吲哚啉酮化合物具有开发新抗菌药物的良好潜力？我们将确定我们目前的先导化合物的一般作用机制。我们还将制备其他类似物，以确定我们的异吲哚啉酮衍生物的一般结构活性关系。我们的研究将显示我们是否能够制备适合在II期研究中进一步开发的选择性和可药用化合物。具体来说，我们计划通过确定我们的先导化合物是否干扰蛋白质、RNA和DNA的合成速率来确定异吲哚啉酮类的作用机制。我们还将评估我们的先导化合物诱导耐药性的能力，并确定我们的先导化合物与已知作用机制的抗生素的协同作用和拮抗作用。我们还将制备一组高度集中的先导化合物类似物，以确定关键芳环周围的最佳取代模式。公共卫生相关性：治疗细菌感染的能力已经受到普通细菌对抗生素日益增长的耐药性的影响;这已经成为一个重大的公共卫生问题。我们已经确定了一种新的结构类型的抗菌剂，并将研究其作用机制，并准备一组选择的类似物来评估抗菌活性。如果成功，该项目将提供一种新的抗菌剂，以解决抗生素耐药性问题。

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.