Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global public health problem, claiming nearly 2 million lives and with more than 8 million new cases recorded each year. The development of drugs that act on novel targets and by diverse mechanisms of action is urgently needed to address the common problems of relapse rates and drug resistance associated with the lengthy treatment (6 months) required for cure. A key to shortening the duration of drug therapy is believed to lie in drugs that target essential pathways in non-replicating bacteria. Current anti-TB drugs are mainly effective against actively replicating or metabolically active bacteria but much less against the non-replicating subpopulations residing within complex immunological structures such as the granuloma. Mtb persistence within granulomatous lesions is still poorly characterized and a clear understanding of its molecular mechanisms may provide an opportunity for the discovery of effective new drug targets for control of the disease. We have identified phenoxyalkylimidazoles (PAI), inhibitors of ubiquinone cytochrome C oxidoreductase QcrB, as a new class of potent anti-TB agents with activity against both replicating and non-replicating Mtb in vitro. We propose to apply a combination of chemistry and microbiology techniques to identify PAI series pharmacophore for QcrB-targeted activity and characterize their mode of action against Mtb under replicating and non-replicating conditions. We will evaluate their properties and conduct in vivo assessment of exposure and efficacy in an animal model of infection. Knowledge of a detailed mechanism of cidality of these agents against Mtb and their mode of interaction with QcrB as the target, especially under non-replicating conditions should be insightful to studies of TB biology and a starting point for drug discovery and development to address persistence.

Public Health Relevance

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem worldwide, claiming nearly 2 million lives and recording more than 8 million new cases each year. A major problem is a prolonged duration of treatment which is mainly attributed to the presence of subpopulations of non-replicating, drug-tolerant or persistent mycobacteria (NRP). We propose to develop optimized analogs of a novel class of agents (phenoxyalkylimidazoles) that target QcrB with potent activity against Mtb and use them as probes for studies of underlying mechanism of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI107626-02
Application #
8974251
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Boyce, Jim P
Project Start
2014-12-01
Project End
2017-11-30
Budget Start
2015-12-01
Budget End
2017-11-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Infectious Disease Research Institute
Department
Type
DUNS #
809846819
City
Seattle
State
WA
Country
United States
Zip Code
98102