Tuberculosis is a leading AIDS-associated, opportunistic infection and globally it has been estimated that twenty percent of AIDS patients die from tuberculosis. In this study we propose to explore and develop a novel class of nitroaromatic anti-tuberculosis agents. This series of compounds is particularly attractive for Tuberculosis drug development because: they are active against slow growing / latent bacteria;these compounds have extremely potent anti-tuberculosis activity;they are not cross resistant with existing front line agents;synthetically they are a tractable series such that modifications to alter sites of metabolism can easily be incorporated;their ease of synthesis has the potential to produce to an inexpensive drug. The current drawback to this series is the low in vivo efficacy due to metabolic instability and low bioavailability. However, we feel due to the difficulties in discovering and developing novel anti-tuberculosis agents that are active against the latent state of TB infection, it is more beneficial to pursue studies to overcome the bioavailablity issues on a drug series that has already demonstrated excellent inhibitory activity against the latent state of infection than attempt to identify a new class of compounds. In the past funding period multiple rounds of optimization allowed us to: develop a detailed structure-activity relationship based on the MIC data;gain an understanding of the PK/PD parameters required for this series to be successful in vivo;and develop a well defined approach for the advancement of this series.
The aims of this proposal are: (i) To develop further generations of compounds that improve the metabolic stability and overall bioavailability of our lead compound. (ii) To select compounds with the best chance for success in in vivo efficacy studies by a detailed pharmacokinetic evaluation and microbial assessment of the emerging leads. The SAR obtained in these studies will be used in the design of future generations of lead compounds. (iii) To evaluate the in vivo efficacy of compounds selected and perform mechanism of action studies on select lead compounds. Ultimately, through rigorous screening and iterative drug design we hope to develop compounds in this study that have good in vivo efficacy, are active against latent TB, and have the potential to advance to preclinical trials.

Public Health Relevance

We propose to develop a novel class of selective anti-tuberculosis agents. These inhibitors will have the potential to treat latent subpopulations of M. tuberculosis in infected individuals and thereby shortening the required time of therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062415-09
Application #
8294430
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Boyce, Jim P
Project Start
2004-05-20
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$613,591
Indirect Cost
$114,260
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
North, E Jeffrey; Jackson, Mary; Lee, Richard E (2014) New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics. Curr Pharm Des 20:4357-78
Rakesh; Bruhn, David F; Scherman, Michael S et al. (2014) Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis. PLoS One 9:e87909
Trivedi, Ashit; Lee, Richard E; Meibohm, Bernd (2013) Applications of pharmacometrics in the clinical development and pharmacotherapy of anti-infectives. Expert Rev Clin Pharmacol 6:159-70
North, E Jeffrey; Scherman, Michael S; Bruhn, David F et al. (2013) Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties. Bioorg Med Chem 21:2587-99
Hurdle, Julian G; O'Neill, Alex J; Chopra, Ian et al. (2011) Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections. Nat Rev Microbiol 9:62-75
Sun, Dianqing; Scherman, Michael S; Jones, Victoria et al. (2009) Discovery, synthesis, and biological evaluation of piperidinol analogs with anti-tuberculosis activity. Bioorg Med Chem 17:3588-94
Rakesh; Sun, Dianqing; Lee, Robin B et al. (2009) Synthesis, optimization and structure-activity relationships of 3,5-disubstituted isoxazolines as new anti-tuberculosis agents. Eur J Med Chem 44:460-72
Budha, Nageshwar R; Lee, Robin B; Hurdle, Julian G et al. (2009) A simple in vitro PK/PD model system to determine time-kill curves of drugs against Mycobacteria. Tuberculosis (Edinb) :
Hevener, Kirk E; Ball, David M; Buolamwini, John K et al. (2008) Quantitative structure-activity relationship studies on nitrofuranyl anti-tubercular agents. Bioorg Med Chem 16:8042-53
Hurdle, Julian G; Lee, Robin B; Budha, Nageshwar R et al. (2008) A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents. J Antimicrob Chemother 62:1037-45

Showing the most recent 10 out of 14 publications