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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054193-02
Application #
6852675
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Lambros, Chris
Project Start
2004-02-15
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$331,951
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
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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
Moraski, Garrett C; Seeger, Natalie; Miller, Patricia A et al. (2016) Arrival of Imidazo[2,1-b]thiazole-5-carboxamides: Potent Anti-tuberculosis Agents That Target QcrB. ACS Infect Dis 2:393-8
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
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 ?-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

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