Understanding stress and methods to relieve stress in microbes could eventually lead to effective drugs against mycobacteria — a family of bacteria that cause a range of infections and diseases including tuberculosis.
Just as humans destress through music, food or holidays, the single-cell bacteria too destresses when it ‘recognises’ factors that cause it stress.
Among the key proteins in action during times of stress is ‘Rel’ protein, which was studied in detail by Dipankar Chatterji and his group from the Molecular Biophysics Unit at the Indian Institute of Science (IISc), Bengaluru.
In a paper published recently in the Federation of European Biochemical Societies Journal, the team unravels the working of the Rel protein in Mycobacterium smegmatis — a cousin of the harmful tuberculosis-causing strain.
Currently, when faced with an atmosphere of antibiotics, pathogens such as mycobacteria produce ‘alarmones’ like guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp). These compounds slow down the growth rate of the bacteria — in the same manner that the human body slows down all but its essential processes during cold or heat — and allows the bacteria to adapt to unfavourable conditions.
Having worked on the protein for over 15 years, Dr. Chatterji has identified a novel site in the Rel protein that binds to its product pppGpp. When the alarmone levels produced by the bacteria reach a threshold, pppGpp binds itself to Rel enzyme and shuts down the production of fresh alarmones.
The identification of the binding site has tremendous value for anti-tuberculosis therapy, says Dr. Chatterji. By synthesising the exact residues in the enzyme that is used by pppGpp to bring alarmone synthesis to a halt, the stress response of the bacteria can be effectively halted.
“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,” he says.
