Toxin-antitoxins & RpsA in TB drug resistance & persistence with HIV

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DESCRIPTION (provided by applicant): 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.