Design of antituberculosis agents that target siderophore biosynthesis

描述（由申请人提供）：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螯合剂（铁载体）负责从人类宿主获得铁，这一过程对结核分枝杆菌（MTb）的存活至关重要，分枝杆菌素已被提出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素在生长和毒力方面的关键作用。抑制分枝杆菌素的生物合成预计会阻断铁的获取，导致细菌死亡，因为结核分枝杆菌的内部铁储备被耗尽。

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.