Transcriptional regulation in M. tuberculosis

In Collaboration with Prof. Neil Stoker and Dr Sharon Kendall, Royal Veterinary College, London

We have recently showed that the essential transcriptional regulator KstR, which has previously been implicated in pathogenesis, directly controls the expression of many lipid metabolism genes in M. tuberculosis. Additionally, a similar transcriptional regulator, KstR2, has also been identified to control a smaller regulon. KstR and KstR2 both belong to the TetR family of transcriptional regulators, and our hypothesis is that the activation of KstR and/or KstR2 is triggered by lipid ligands derived from the human host, triggering bacterial adaptation to the intracellular environment. We are aiming to structurally and functionally characterise these transcription factors to discover more about their mode of action.

Drug targets from M. tuberculosis

In Collaboration with Prof. Ted Baker

We have recently solved the structure of two enzymes known to be essential for the bacterium to cause disease: anthranilate phosphoribosyl transferase (AnPRT; TrpD), the enzyme which catalyses the second committed step in tryptophan biosynthesis, and salicylate synthase (MbtI) which catalyses the production of salicylate, essential for the production of the siderophore mycobactin.. Through a combination of in silico modelling and in vitro assay, we have identified a set of weak AnPRT inhibitors, and we are set to embark on the structure-guided synthesis of potent inhibitors of both enzymes, which may be useful anti-mycobacterial agents of the future.

The hypoxic response of M. tuberculosis.

In Collaboration with Prof. Ted Baker

Decreased oxygen concentration is thought to be important for the bacterium’s entry into an antibiotic-resistant, non-replicating persistent (NRP) state in its human host, allowing it to persist for long periods of time, sometimes decades, before it re-emerges to cause disease. We have focussed on a set of proteins that are very highly expressed in response to hypoxia, but whose functions remain unclear, and have solved the structure of one of them. We are testing whether they interact with each other to form complexes, and pursuing hypotheses regarding their biochemical functions.