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Applied Sciences Dept.

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  • Role of acetylation in pathophysiology of mycobacteria

Mycobacterium tuberculosis (Mtb) is an obligate human intracellular pathogen that causes Tuberculosis (TB) leading to millions of death annually worldwide. A remarkable feature of the pathogen is its ability to persist within the host for decades despite an impressive onslaught of stresses. Although active mycobacterial infection can be effectively treated with multidrug anti-mycobacterial therapy, the shortest antibiotic regimens that will achieve reliable clinical cure remain for atleast six months. Hence, a major goal for improving the TB treatment is to develop agents that will shorten the anti-mycobacterial therapy. One such model of TB drug development may hold that inhibitors of proteins necessary for Mtb to tolerate the harsh in vivo environment of the host would be promising candidates to shorten therapy. Hence, we need to first identify the proteins that are involved in the stress induced response of Mycobacteria.

In an infected host, Mtb resides primarily within the phagosomes of macrophages. In activated macrophages, Mtb encounters a variety of stresses including low pH, nitric oxide, hypoxia and others. It can be speculated that the increased level of cAMP at an early stage of infection might lead to increased acetyltransferase activity of GNAT proteins, since the level cAMP was reported to be significant for acetyltransferase activity. Since, it was evident that acetylation can change the DNA binding affinity of transcription factors, the alteration in Mycobacterial transcriptional profile of a wide range of genes in response to acid stress and hypoxia further reinforce the involvement of acetylation in stress induced responses of Mycobacteria. It is evident that Mtb is exposed to low or restricted nutrient concentrations in the host and it is very likely the pathogen might regulate its metabolism during infection. Since, the proteome-wide lysine acetylation profiling has revealed that the activities of metabolic enzymes are presumably regulated by acetylation in Mtb, it further emphasize the active involvement of acetylation in stress induced response of Mycobacteria during infection.

So, in this project we will try to identify mycobacterial proteins that are differentially regulated by acetylation in response to acidic and hypoxic stress with the prediction that these proteins would be involved during infection. We will further explore the molecular mechanisms and importance of acetylation of these proteins during infection. The knowledge may further lead to the development of therapeutic agents that target Mycobacterial components produced by these stresses during the infection.

  • Role of acetylation in multidrug resistance of mycobacteria