Design/Syntheses/Studies/Novel Antituberculosis Agents

设计/合成/研究/新型抗结核药物

• 批准号: 7028302
• 负责人: MARVIN J MILLER
• 金额: $ 32.42万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028302
• 关键词: Mycobacterium tuberculosis; analog; antibiotics; antiinfective agents; chelating agents; chemical conjugate; chemical structure; drug design /synthesis /production; iron; iron metabolism; laboratory mouse; microorganism disease chemotherapy; microorganism metabolism; pharmacology; tissue /cell culture; tuberculosis

DESCRIPTION (provided by applicant): Design, syntheses and studies of novel anti-tuberculosis agents based on biologically essential mycobacterial iron sequestration processes are proposed. Assimilation of iron is essential for most living organisms. Thus, microbes, including Mycobacterium tuberculosis, have evolved very selective and specific methods to sequester physiologically essential iron. The general hypothesis of this proposal is that the iron sequestration process utilized by Mycobacterium tuberculosis can be exploited as an "Achilles' heel" for the development of novel antituberculosis agents. Though this concept has been considered, no laboratory has previously been able to synthetically access the relevant compounds for related studies. The specific aims are the following. 1. Design, syntheses and studies of focused sets of analogs of natural iron chelators (mycobactins) used by M. tuberculosis to determine if analogs can inhibit iron acquisition, thus, inducing microbe selective iron starvation and microbe death (confirmation of "Snow's Hypothesis"). The analog design will build on our preliminary findings that selective structural variation of mycobactins does produce novel antiTB agents. Thus, practical scale syntheses of lead compounds will be followed by focused structural modification. The synthetic work will be complemented by full chemical and physical characterization of samples, including determination of the iron binding affinity of the mycobactin analogs and conjugates as well as their ability to bind iron from media. 2. Syntheses and studies of a focused and limited set of mycobactin (siderophore)- antibiotic conjugates capable of selective microbe cell transport and drug delivery. All conjugates can be prepared in straightforward fashion (one to three steps) from our already synthesized lead compounds. 3. In Vitro and in vivo biological evaluation of samples for antituberculosis activity, growth inhibition or promotion of other selected mycobacteria and related studies, including gross toxicity, will be performed to determine the mode of action of new compounds with anti-TB activity. Taken together, these studies will determine the feasibility of developing new antituberculosis agents with a novel mode of action related to the required iron uptake processes needed by mycobacteria, including M. tuberculosis.

描述（由申请人提供）：提出了基于生物学上必不可少的分枝杆菌铁隔离过程的新型抗结核药的设计，合成和研究。铁的同化对于大多数生物体都是必不可少的。因此，包括结核分枝杆菌在内的微生物已经进化出非常有选择性和特定的方法来隔离生理上必不可少的铁。该提议的一般假设是，结核分枝杆菌所使用的铁隔离过程可以被用作“阿喀琉斯”脚跟，以开发新的抗结核药。尽管已经考虑过这个概念，但以前没有实验室能够合成访问相关研究的相关化合物。具体目的是以下。 1。结核分枝杆菌使用的天然铁螯合剂类似物（Mycobactins）的集合，合成和研究，以确定类似物是否可以抑制铁的获取性，因此，诱导微生物选择性铁饥饿和微生物死亡（确认“ Snow的假设”）。模拟设计将基于我们的初步发现，即霉菌的选择性结构变化确实会产生新颖的抗抗Batent。因此，铅化合物的实际规模合成将进行集中的结构修饰。合成工作将通过样品的完全化学和物理表征来补充，包括确定菌根类似物和缀合物的铁结合亲和力，以及它们结合培养基的铁的能力。 2。对聚焦且有限的菌根（铁载体）的合成和研究 - 能够选择性微生物细胞运输和药物递送的抗生素结合物。所有共轭物都可以与我们已经合成的铅化合物以简单的方式（一到三个步骤）制备。 3。在体外和体内生物学评估样品的抗结核活性，生长抑制或促进其他选定的分枝杆菌及其相关研究（包括毒性），以确定具有抗TB活性的新化合物的作用方式。 综上所述，这些研究将决定开发新的抗结核剂的可行性，其新型作用方式与分枝杆菌所需的铁摄取过程有关，包括结核分枝杆菌。