More than two billion people have tuberculosis! This proposal focuses on two approaches that will lead to the development of needed new antiTB agents. The first, studies associated with mycobactins, compounds that regulate assimilation of iron that is essential for growth and virulence of Mycobacterium tuberculosis, led to the discovery of simple, easily synthesized, potent, non-toxic, remarkably selective small molecule antiTB agents, including imidazo[1,2-a]pyridines, the development of which will be the second goal. The results described in this application indicate that at least three methods can be used to exploit the iron assimilation process as a potential """"""""Achilles'heel"""""""" to develop novel antiTB agents: (a) interference (inhibition) of mycobacterial iron assimilation, (b) utilization of iron assimilation for TB-selective drug delivery, and (c) use of the essential Fe(+3) to Fe(+2) reduction to generate reactions that cause intracellular mycobacterial damage. Moreover, access to high throughput antiTB screening of all targeted synthetic compounds, intermediates and components led to the discovery of new types of potent (sub micromolar) simple small molecule antiTB agents, most notably, oxazolines and oxazoles derived from studies of the oxazoline mycobactin component and new imidazo[1,2-a]pyridine analogs (with low nanomolar antiTB activity against multidrug resistant (MDR) and extreme drug resistant (XDR) TB!). These significant results encourage further development using three specific aims.
Aim 1. Optimize our potent, non-toxic, selective, metabolically stable and inexpensive small molecule antiTB agents. Using the effective chemistry developed (and described new syntheses) we will extend SAR studies, measure selectivity and toxicity, and modulate metabolism of our novel small molecule leads (especially the new very potent and metabolically stable imidazo[1,2-a]pyridines) for enhanced antiTB efficacy. The chemistry will facilitate syntheses of mycobactin drug conjugates (aim 2).
Aim 2. Design, synthesize and study mycobactin-derived inhibitors of iron assimilation of tuberculosis and mycobactin-drug conjugates. The goal is to demonstrate the fundamental principle that exploitation of the iron assimilation that is absolutely essential for mycobacterial growth and virulence can provide new approaches to development of antiTB agents while assessing the underexplored """"""""Trojan Horse"""""""" approach.
Aim 3. Evaluate all lead compounds using appropriate in vitro and in vivo pre-clinical studies. Through our extensive collaborations, we will evaluate all samples for antiTB activity [including MDR (multi-drug resistant) and XDR (extreme drug resistant) strains of M. tuberculosis]. We will also perform related studies, including gross toxicity, metabolism, pharmacokinetics (PK), maximum tolerated dose (MTD) and mode of action studies of new compounds with antiTB activity. A highly qualified team of coworkers and collaborators has been assembled to accomplish the goals.
More than two billion people have tuberculosis! Design, syntheses and studies of novel antiTB agents described in this proposal are based on discoveries made from studies of the essential mycobacterial iron sequestration processes. In addition to indicating that such focused studies can produce novel antiTB compounds, progress from the last grant period produced novel, easily synthesized, metabolically stable, small molecules with potent antiTB activity that merit further study and development.
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