The goal of this R21 project is develop novel approaches to identify inhibitors of Mycobacterium tuberculosis that will have potent in vivo activity. The hypothesis underlying this proposal is that inhibitors that have increased activity i the setting of oxidative or nitrosative stress will be active during human infection, where these stresses are generated by host phagocytes and function as major antibacterial effectors. The goal of this research will be addressed through two specific aims. First we will develop and perform small molecule screens to identify inhibitors that are active in the presence of oxidative or nitrosative stresses. Second, to examine whether stress-potentiated inhibitors are likely to be active in vivo, we will determine their activity in a human in vitro granuloma model of M. tuberculosis infection. Completion of these aims will provide evidence as to whether inhibitors that are active in the presence of stress, or potentiated by stress, are likely to be good candidates for new anti-tuberculosis drugs. These data will provide the basis for performing large-scale stress- based screens to identify inhibitors that may be developed as candidate new drugs for tuberculosis.

Public Health Relevance

Tuberculosis is difficult to treat, requiring prolonged multi-drug therapy;treatment of drug-resistant tuberculosis, which is increasing globally, is even more challenging. New drugs for tuberculosis treatment are urgently needed to shorten treatment duration and provide better treatment for drug-resistant TB. This project will develop and test new methods to identify inhibitors that may lead to new approaches to treating tuberculosis. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI097881-02
Application #
8500180
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Boyce, Jim P
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$204,450
Indirect Cost
$86,950
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115