The increasing MDR/XDR-TB problem poses a major threat to TB control, and HIV infection threatens to further aggravates the problem. Mycobacterial persistence underlies lengthy therapy and is often the root cause for drug resistance due to poor compliance to lengthy therapy, thus there is significant interest to develop novel drugs based on new mechanisms of drug resistance and persistence. WhiB7 is a transcription factor, which controls a region of 8 genes including tap (Rv1258c), encoding an efflux protein for tetracycline and aminoglycoside excretion, and plays a key role in the intrinsic antibiotic resistance and possibly tolerance or persistence. Treated chronic bacterial or fungal infections harbor variants with increased antibiotic tolerance associated with polymorphisms in toxin-antitoxin (TA) genes involved in persistence. Clinical isolates of M. tb harbor mutations in whiB7, tap and TA genes, but the role of these mutations in drug tolerance/persistence is unknown. Furthermore, a new mechanism of pyrazinamide (PZA) resistance due to mutations in drug target RpsA involved in trans-translation was recently identified, but the role of rpsA mutations in contributing to PZA resistance is unclear. While PZA resistance in MDR-TB, which is correlated with poor treatment outcome, ranges from 20-80% in some parts of the world, the frequency of PZA resistance in Russian MDR-TB strains is unknown. Therefore, the project will first analyze drug resistant clinical isolates of M. tb in Russian collection for polymorphisms in whiB7, tap, TA modules and RpsA and determine the frequency of PZA resistance in Russian MDR-TB strains. Second, the role of mutations in whiB7, tap, TA modules and rpsA in drug resistance and persistence/tolerance to antibiotics and stresses and survival in macrophages will be addressed. The proposed studies will fill in critical gaps in knowledge of drug resistance and persistence in M. tb. The outcome of this study will help to understand the mechanisms of drug resistance and persistence and provide useful information for design of persister drugs for shortening the TB treatment and improved treatment of drug-resistant TB.

Public Health Relevance

The increasing drug resistant TB and mycobacterial persistence and HIV co-infection pose major threat for TB control. This project aims to address the role of several candidate genes in drug resistance and persistence in clinical isolates of M. tuberculosis in Russia where there is significant drug-resistant TB problem. The outcome of the study will help to understand mechanisms of drug resistance and persistence and provide useful information for design of new drugs and for improved treatment of drug-resistant TB.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI108535-01
Application #
8605655
Study Section
Special Emphasis Panel (ZRG1-AARR-H (51))
Program Officer
Lacourciere, Karen A
Project Start
2014-04-04
Project End
2016-03-31
Budget Start
2014-04-04
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$243,000
Indirect Cost
$93,000
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218