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ReLieving stress: understanding the regulation of Mycobacterial stress response

All of us have been stressed out at some point in life, and have our own ways to deal with it. We listen to music, head out for a run, or to the ice-cream store. Bacteria are no different. But, imagine – recognising that there is a stressor, and dealing with it all happens within a tiny bacterium.

A series of proteins get busy when a bacterium is stressed. One such protein is ‘Rel’, and this is the one Prof Dipankar Chatterji and his group from the Molecular Biophysics Unit at the Indian Institute of Science (IISc), Bengaluru have been studying.

“Bacteria become very infective when under stress like starvation, their growth rate becomes tremendously slow”, explains Dr. Chatterji. This slow growth rate is one of the reasons that pathogens like Mycobacteria evade killing by antibiotics. During an infection, the bacteria come under pressure due to the relentless attack of the host immune system. It is under such conditions of stress that bacteria produce ‘alarmones’ like guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp). These compounds allow the bacteria to adapt to conditions that are unfavourable for normal growth of the organism.

Working on Mycobacterium smegmatis, a harmless cousin of the disease causing Mycobacterium tuberculosis, the team have worked out how the protein ‘Rel’ is controlled inside the bacterium.

The alarmones are produced by an enzyme called Rel, found not only in Mycobacteria but all other bacterial species. One of the main focuses of research today is into drugs that can inhibit Rel, thereby impeding the bacteria’s ability to adapt to stress conditions. Dr. Chatterji’s group has worked extensively on the Rel protein of Mycobacterium smegmatis for fifteen years, being the first to characterize the enzyme at the molecular level. In their recent study, the group has identified a novel site in the Rel protein that binds to its product pppGpp. The binding appears to inhibit the activity of the Rel enzyme, and as a result, could be responsible for tuning down the stress response of the cell.

Showing that the product of the Rel enzyme binds to the enzyme itself opens up a new paradigm of enzyme regulation called ‘feedback inhibition’. “This is the first report of (Rel) modulation by pppGpp”, says Dr. Chatterji. The feedback inhibition allows the cell to optimize the number of alarmone molecules it produces. When the alarmone levels reach a threshold, pppGpp binds to the Rel enzyme, shutting down the production of fresh alarmones. The study has also identified the exact residues in the enzyme that is used by pppGpp to bring alarmone synthesis to a halt.

This study could prove invaluable in the hunt for an effective anti-tuberculosis therapy. Speaking about the impact of his study on drug development, Dr. Chatterji says, “In 2012, a drug against Rel was introduced, but it works only at very high concentrations. We think there is a tremendous opportunity to improve (these drugs)”.

The discovery of the regulatory mechanism of Rel and the exact sites that are responsible for its inhibition goes a long way towards designing a drug that can effectively silence the bacterial stress response. Dr. Chatterji and his group have uncovered key information that could help improve the antibiotics that we are given today.

About the author:
Dr. Dipankar Chatterji is a Professor at the Department of Molecular Biophysics at the Indian Institute of Science, Bengaluru. Phone: +91-080-2293-2836

About the paper:
The study titled ‘Novel pppGpp binding site at the C-terminal region of the Rel enzyme from Mycobacterium smegmatis’ was published in ‘The FEBS journal’ online on 3rd August 2015.