Faculty

Our group is interested in understanding molecular mechanisms in three
biological areas: 1) DNA replication in Mycobacterium tuberculosis, 2)
persistence of M. tuberculosis in the human host, 3) drug resistance
of M. tuberculosis and 4) DNA remodeling by human XPB helicase. A
combination of structural biology (X-ray crystallography) and in vitro
biochemical and biophysical techniques by our group and complementary biological studies by our collaborators serve as a multi-disciplinary approach to elucidation of these complex systems.

1.  We study a multiprotein machinery that initiates DNA replication,
called a primosome, in M. tuberculosis. We expect that understanding
mechanistic and structural details of this essential process will
eventually lead to the discovery of therapeutically promising DNA
replication inhibitors for the deadliest killer among bacteria.

2. One-third of the human population is infected with M. tuberculosis
(in a so-called latent form) and 5-10 % of the infected individuals
will develop active tuberculosis. After infecting a human, M.
tuberculosis can enter a persistent state (or states) inside a
macrophage. This infection is maintained even upon macrophage
activation when the bacterium encounters a variety of stresses, such
as oxidation and acidification. In collaboration with Dr. Sabine Ehrt
at Weill Medical College of Cornell University, we study mechanisms
that enable M. tuberculosis to resist these stresses.

3. Tuberculosis is resistant to many conventional antibiotics, such as penicillin and requires a special set of drugs to be treated. Some M. tuberculosis strains are resistant even to these drugs and are deadly. In collaboration with Dr. Sylvie Garneau-Tsodikova at the UM, we investigate the mechanism of resistance of TB to aminoglycosides, drugs of the last resort in TB treatment.

4. Human XPB helicase is involved in two distinct biological processes: transcription initiation and nucleotide excision repair (NER). In both, XPB performs essential ATPase-driven DNA remodeling. Mutations in XPB are manifested as severe genetic syndromes: xeroderma pigmentosum (XP), Cockayne Syndrome (CS) or trichothiodystrophy (TTD). We study the mechanism of DNA remodeling by XPB and its regulation.

Tsodikov Research Lab

Awards

Representative Publications

1. Chen W, Biswas T (first co-author), Porter VR, Tsodikov OV*,
   Garneau-Tsodikova S*. (2011) Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB. Proc. Natl. Acad. Sci. U. S. A.,108, 9804-9808. (* co-corresponding authors)

2. Tsodikov OV*, Biswas T*. (2011) Structural and thermodynamic signatures of DNA recognition by Mycobacterium tuberculosis DnaA. J. Mol. Biol., 410, 461-476. (* co-corresponding authors)

3. Biswas T, Small J, Vandal O, Odaira T, Deng H, Ehrt S*, Tsodikov OV*. (2010) Structural insight into serine protease Rv3671c that protects M. tuberculosis from oxidative and acidic stress. Structure, 18, 1353-1363. (*co-corresponding authors)

4. Biswas T, Pero JM, Joseph GC, Tsodikov OV. (2009) DNA dependent ATPase activity of bacterial XPB helicases. Biochemistry, 48, 2839-2848.

5. Biswas T, Tsodikov OV. (2008) Hexameric ring structure of the N-terminal domain of Mycobacterium tuberculosis DnaB helicase. FEBS J., 275, 3064-3071.