Design/Syntheses/Studies/Novel Antituberculosis Agents

描述(由申请人提供)：建议设计、合成和研究基于生物必需的分枝杆菌铁固定方法的新型抗结核药物。铁的同化对大多数生物来说是必不可少的。因此，微生物，包括结核分枝杆菌，已经进化出非常有选择性和特殊的方法来隔离生理上必需的铁。这一建议的一般假设是，结核分枝杆菌利用的铁隔离过程可以被用作开发新的抗结核药物的“阿喀琉斯之踵”。尽管已经考虑过这一概念，但以前还没有一家实验室能够合成相关化合物进行相关研究。具体目标如下。 1.设计、合成和研究结核分枝杆菌使用的天然铁络合剂类似物(霉菌素)的设计、合成和研究，以确定类似物是否能抑制铁的获取，从而导致微生物选择性铁饥饿和微生物死亡(证实了斯诺的假设)。模拟设计将建立在我们的初步发现的基础上，即分枝杆菌菌素的选择性结构变异确实会产生新的抗结核病药物。因此，先导化合物的实际规模合成之后将有重点的结构修饰。除了合成工作外，还将对样品进行全面的化学和物理表征，包括测定mycobactin类似物和结合物的铁结合亲和力以及它们从介质中结合铁的能力。2.具有选择性微生物细胞转运和药物输送能力的一组聚焦和有限的Mycobactin(铁载体)-抗生素结合物的合成和研究。所有的连接物都可以直接从我们已经合成的先导化合物中制备出来(一到三步)。3.将在体外和体内对样本进行抗结核活性、抑制或促进其他选定分枝杆菌生长的生物评价，并进行相关研究，包括大体毒性，以确定具有抗结核活性的新化合物的作用模式。 综上所述，这些研究将确定开发新的抗结核药物的可行性，这种新的作用模式与包括结核分枝杆菌在内的分枝杆菌所需的铁摄取过程有关。

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.