My current work as a PhD student at Royal Veterinary College (University of London) is focussed on an elusive group of regulators, the TetR family of transcriptional regulators (TFTRs) in Mycobacterium tuberculosis and Mycobacterium bovis, the cause of tuberculosis in humans and cattle respectively (though there is crossover). M. tuberculosis is the leading cause of death by an infectious disease in the world, with one death every 15 seconds due to tuberculosis. It is estimated that ⅓ of the world is infected with M. tuberculosis and from 2014 infections data (United Nations, 2015), there were an estimated 9.6 million active TB infections, with ~500,000 multi-drug resistant. This led to an estimated figure of 1.5 million deaths.

The difficulty with TB infections lies with both long treatment regimes (due to slow growth of the bacterium) and availability of a vaccine (M. bovis BCG), but with limited efficiency, especially in high prevalence areas.

My work focusses specifically on the TFTRs of Mycobacteria. Very little is known about the function of each individual TetR, though some have been characterised: ethR (Baulard et al. 2000)kstR (Kendall et al. 2007)kstR2 (Kendall et al. 2010)bkaR (Balhana et al. 2013) and most recently, inbR (Yang et al. 2015).

In M. tuberculosis alone, there are 52 TetR regulators, more than any other regulators (Figure 1). These provide an attractive group of genes to study, to both determine their function in relation to how M. tuberculosis survives within the host and even the possibility of targeting them for new anti-tuberculosis drugs/vaccines.

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Figure 1: A comparison of all members of the Helix Turn Helix (HTH) protein family in various Mycobacteria. TetR group are classed as TFTR group (red arrow).

Upon bioinformatic analyses and literature searching, promising targets to study the function were selected to work on, without current work focussing on 3 TetR regulators in M. tuberculosisRv0135c, Rv0775 and Rv1255c. These TetRs are our main focus, due to their association with cytochrome P450s (CYPs), a group of enzymes involved in a wide variety of functions from cholesterol metabolism to drug detoxification.

Our work is now focusing on these Cytochrome Associated TetRs (CATs) using a range of techniques including GFP reporter assays, flow cytometry, ligand binding studies, CRISPR interference, RNA-Seq and additional work. Our hope is to further understand the way in which M. tuberculosis is able to regulate CYPs and its metabolism within the host.