Researchers discover the process behind bacteria's coping strategies

A new study has revealed crucial information on bacteria's coping strategies, paving the way for novel approaches to tackle infection.

For over forty years scientists have known that when bacteria are under stress they produce a molecule called guanosine tetraphosphate (ppGpp) that allows them to survive in difficult conditions and even resist the action of antibiotics.  This molecule triggers a pattern of genetic activity, switching on and off the appropriate genes that instruct the bacteria to stop growing and use minimal resources. Until now, the control mechanisms that allowed bacteria to accumulate ppGpp have remained something of a mystery but a new study published in Nature Communications by researchers from Imperial College London has shed light on this important area.

The discovery came about when researchers put the ubiquitous Escherichia coli (E. coli) bacteria under stress by starving the bugs of nitrogen, which is essential for growth. They discovered that a gene control protein called NtrC plays a central role in the process that controls the levels of the ppGpp molecule, which in turn triggers bacteria’s coping strategies.

When bacteria are stressed they ‘lie low’ and minimise their activity. Antibiotics target bacteria by sensing their activity so when bacteria are in ‘coping mode’ the drugs can no longer detect targets in the bacteria and take effect. Chronic or long-lasting infections are often caused by bacteria applying these efficient coping strategies and ‘going into hiding’.  If scientists can find ways to block this coping mechanism, then bacteria will remain exposed and vulnerable so antibiotics can target them effectively.

 “It was a revelation,” said lead author Professor Sivaramesh Wigneshweraraj from the Department of Medicine at Imperial College London. “We have known for a long time that when bacteria run out of nutrients they adapt to the situation through the release of ppGpp. So we knew the cause and the effect but we didn’t know what happened in between. Now we have shone a light into the engine room of bacteria’s coping mechanism by discovering that the protein NtrC plays an essential role in how bacteria cope under conditions of nitrogen starvation. This is a hugely important finding for the fundamental biology of bacteria and could have significant practical implications in terms of improving and developing drugs to fight bacterial infections.”

When bacteria are under stress of any type, they respond by switching on the relA gene, which then produces ppGpp. This molecule acts as a ‘messenger’ triggering a pattern of genetic activity to produce an effective coping strategy. When the research team were investigating the NtrC protein, which is a well-known master gene regulator that allows bacteria to cope with nitrogen starvation, they unexpectedly discovered that NtrC bound to a site close to the relA gene. They then demonstrated that NtrC is the trigger that switches on the relA gene, which allows ppGpp to start the coping process.

Dr. Daniel Brown, a postdoctoral research fellow from the Department of Medicine, Imperial College London and first author on the study said: “This shows that bacteria have a very efficient way to cope with starvation for nutrients: they use the same gene control protein NtrC to simultaneously turn on genes that allow them to scavenge for new nitrogen sources and to activate a response that promotes longer-term survival. This gives them the best chance of survival while the status of their environment is uncertain. It seems as though they are hedging their bets, something that we may be able to exploit from further study.”

The discovery came out of a larger Biotechnology and Biological Sciences Research Council (BBSRC) funded research programme with Professors Martin Buck and Michael Stumpf, Faculty of Natural Sciences at Imperial College London. This programme aims to understand how bacteria manage their nitrogen economy.

Professor Martin Buck said: “Clearly we have much to learn about the ways bacteria can manage stressful conditions, relevant to their survival in the environment as well as in infection settings.”

The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC). Professor Wigneshweraraj is a recipient of a Wellcome Trust Investigator Award and principal investigator at the MRC Centre for Molecular Bacteriology and Infection.

Reference: Brown et al. ‘Nitrogen stress response and stringent response are coupled in Escherichia coli’. Nature Communications (2014) doi: 10.1038/ncomms5115