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.
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