BRODOLIN Konstantin

Regulation of gene transcription is the principal mechanism underlying appearance of the drug-tolerant, dormant, forms of bacteria and the chronic latent infections like tuberculosis. Transcription is performed in bacteria by the multisubunit enzyme, DNA-dependent RNA polymerase (RNAP), composed of the catalytic core and the sigma subunit which is required for promoter-specific initiation of RNA synthesis. RNAP is a target for the anti-tuberculosis drug, rifampicin (Rif) and the novel drug, fidaxomicin (Fdx, lipiarmycin) used for treatment of nosocomial intestinal infection associated with Clostridium difficile. The sigma subunit of RNAP as well as other transcription factors (e.g. RbpA from M. tuberculosis) are implicated in the generation of resistance in response to the antibiotic treatment. The global objectives of our studies are (1) to understand a role of sigma subunits and the RNAP-binding factors in regulation of genes implicated in antibiotic resistance; (2) to decipher mechanisms of action of the antibiotics targeting RNAP and (3) to decipher molecular mechanisms of resistance/ tolernace to these molecules. Our project is focused on the mechanism of transcription regulation in two most widespread human pathogens: Escherichia coli and Mycobacterium tuberculosis. We also explore the role of the ? subunit in the elementary steps of gene expression such as promoter recognition, RNA synthesis and transcriptional pausing. The results of our study help to understand the molecular basis of antibiotic resistance and may provide a basis for the development of new, more efficient drugs..