Design of antituberculosis agents that target siderophore biosynthesis

描述(申请人提供)：结核病(TB)是世界上由细菌病原体引起的传染病死亡的主要原因。由于结核分枝杆菌(MTB)产生的这些小分子铁络合剂(铁载体)负责从人类宿主获取铁，这一过程对结核分枝杆菌的生存至关重要，因此分枝杆菌毒素已被提议作为结核病药物的新靶点。大量的体外和体内证据支持分枝杆菌菌素对生长和毒力的关键作用。抑制霉菌蛋白的生物合成预计会阻止铁的获取，导致细菌死亡，因为结核分枝杆菌的内部铁库已经耗尽。 我们的长期目标是了解分枝杆菌毒素在体内铁获取中的作用，以及如何将其转化为治疗结核病的药物。这项应用的目的是开发参与分枝杆菌毒素生物合成的两种关键酶的抑制剂，并对它们进行抗结核分枝杆菌的评估。抑制剂的设计是基于一类功能相关的酶，这些酶已经得到了广泛的研究，并且已经有FDA批准的药物。这一应用的中心假设是，通过小分子抑制铁载体的生物合成将是开发新的抗结核药物的有效策略。 预计在完成这项工作后，我们将对控制抑制剂活性、结合、转运、稳定性、新陈代谢和细胞毒性的结构-活性-关系(SAR)建立详细的了解。这一策略也可能适用于其他需要铁载体才能产生毒力的病原体，如鼠疫耶尔森氏菌、炭疽杆菌、铜绿假单胞菌和霍乱弧菌，它们分别是鼠疫、炭疽、机会性感染和霍乱的病原体。因此，本文提出的研究有望对人类健康产生积极影响，并可能额外验证一类针对铁载体生物合成的新型抗生素。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is the leading cause of infectious disease mortality in the world by a bacterial pathogen. The mycobactins have been proposed as novel targets for TB drugs since these small-molecule iron chelators (siderophores) produced by Mycobacterium tuberculosis (MTb) are responsible for obtaining iron from the human host, a process that is essential for the survival of MTb. The critical role of the mycobactins for growth and virulence is supported by substantial in-vitro and in-vivo evidence. Inhibition of mycobactin biosynthesis is expected to block iron acquisition, leading to bacterial death as internal iron stores of MTb are exhausted. Our long-term goal is to understand the in-vivo role of the mycobactins in iron acquisition, and how this can be translated into agents for the treatment of TB. The objective of this application is to develop inhibitors of the two key enzymes involved in the biosynthesis of the mycobactins and to evaluate these against MTb. The inhibitor design is based on a functionally-related class of enzymes that have been extensively studied and for which there is already a FDA approved drug. The central hypothesis of this application is that an inhibition of siderophore biosynthesis by a small molecule will be an effective strategy for developing new anti-TB agents. It is expected that upon completion of this we will have established a detailed understanding of the structure-activity-relationships (SAR) that govern activity, binding, transport, stability, metabolism, and cytotoxicity of the inhibitors. This strategy may also be adapted to other pathogens that require siderophores for virulence such as Yersinia pestis, Bacillus anthracis, Pseudomonas aeruginosa, and Vibrio cholera the causative agents of the plague, anthrax, opportunistic infections, and cholera respectively. Thus, the research proposed herein is expected to have a positive impact on human health and may additionally validate a new class of antibiotics that target siderophore biosynthesis.