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. ? ? ?
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