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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Discovery and Development of Therapeutics Study Section (ADDT)
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Boyce, Jim P
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University of Notre Dame
Schools of Arts and Sciences
Notre Dame
United States
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Cheng, Yong; Moraski, Garrett C; Cramer, Jeffrey et al. (2014) Bactericidal activity of an imidazo[1, 2-a]pyridine using a mouse M. tuberculosis infection model. PLoS One 9:e87483
Moraski, Garrett C; Oliver, Allen G; Markley, Lowell D et al. (2014) Scaffold-switching: an exploration of 5,6-fused bicyclic heteroaromatics systems to afford antituberculosis activity akin to the imidazo[1,2-a]pyridine-3-carboxylates. Bioorg Med Chem Lett 24:3493-8
Wencewicz, Timothy A; Miller, Marvin J (2013) Biscatecholate-monohydroxamate mixed ligand siderophore-carbacephalosporin conjugates are selective sideromycin antibiotics that target Acinetobacter baumannii. J Med Chem 56:4044-52
Moraski, Garrett C; Markley, Lowell D; Cramer, Jeffrey et al. (2013) Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and Nanomolar Activity Against Mycobacterium tuberculosis. ACS Med Chem Lett 4:675-679
Ollinger, Juliane; Bailey, Mai Ann; Moraski, Garrett C et al. (2013) A dual read-out assay to evaluate the potency of compounds active against Mycobacterium tuberculosis. PLoS One 8:e60531
Tiwari, Rohit; Moraski, Garrett C; Krchnak, Viktor et al. (2013) Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents. J Am Chem Soc 135:3539-49
Moraski, Garrett C; Markley, Lowell D; Chang, Mayland et al. (2012) Generation and exploration of new classes of antitubercular agents: The optimization of oxazolines, oxazoles, thiazolines, thiazoles to imidazo[1,2-a]pyridines and isomeric 5,6-fused scaffolds. Bioorg Med Chem 20:2214-20
Miller, Marvin J; Walz, Andrew J; Zhu, Helen et al. (2011) Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria. J Am Chem Soc 133:2076-9
Moraski, Garrett C; Markley, Lowell D; Hipskind, Philip A et al. (2011) Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis Activity. ACS Med Chem Lett 2:466-470
Wu, Chunrui; Miller, Patricia A; Miller, Marvin J (2011) Syntheses and studies of amamistatin B analogs reveals that anticancer activity is relatively independent of stereochemistry, ester or amide linkage and select replacement of one of the metal chelating groups. Bioorg Med Chem Lett 21:2611-5

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