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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI054193-09
Application #
8658791
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Boyce, Jim P
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Majewski, Mark W; Miller, Patricia A; Miller, Marvin J (2016) Studies at the ionizable position of cephalosporins and penicillins: hydroxamates as substitutes for the traditional carboxylate group. J Antibiot (Tokyo) :
Majewski, Mark W; Tiwari, Rohit; Miller, Patricia A et al. (2016) Design, syntheses, and anti-tuberculosis activities of conjugates of piperazino-1,3-benzothiazin-4-ones (pBTZs) with 2,7-dimethylimidazo [1,2-a]pyridine-3-carboxylic acids and 7-phenylacetyl cephalosporins. Bioorg Med Chem Lett 26:2068-71
Moraski, Garrett C; Cheng, Yong; Cho, Sanghyun et al. (2016) Imidazo[1,2-a]Pyridine-3-Carboxamides Are Active Antimicrobial Agents against Mycobacterium avium Infection In Vivo. Antimicrob Agents Chemother 60:5018-22
Tiwari, Rohit; Miller, Patricia A; Chiarelli, Laurent R et al. (2016) Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043. ACS Med Chem Lett 7:266-70
Majewski, Mark W; Watson, Kyle D; Cho, Sanghyun et al. (2016) Syntheses and Biological Evaluations of Highly Functionalized Hydroxamate Containing and N-Methylthio Monobactams as Anti-Tuberculosis and β-Lactamase Inhibitory Agents. Medchemcomm 7:141-147
Ji, Cheng; Miller, Marvin J (2015) Siderophore-fluoroquinolone conjugates containing potential reduction-triggered linkers for drug release: synthesis and antibacterial activity. Biometals 28:541-51
Majewski, Mark W; Cho, Sanghyun; Miller, Patricia A et al. (2015) Syntheses and evaluation of substituted aromatic hydroxamates and hydroxamic acids that target Mycobacterium tuberculosis. Bioorg Med Chem Lett 25:4933-6
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
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

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