Antibacterial toxin discovery could open up new infectious disease treatments

New research reveals weaponry used by bacteria that could be exploited to develop new therapeutic treatments.

The new study, which is published in the journal Cell Host and Microbe, outlines the discovery of a new family of potent toxins, which are fired by a specialised ‘secretion system’ called T6SS.

Scientists were aware that bacteria could kill other bacteria, but until now they did not fully understand how they waged war. To unravel this, researchers from Imperial College London and Academia Sinica in Taiwan studied the plant pathogen Agrobacterium tumefaciens in action within tobacco plants, and explored how it deployed T6SS to attack other bacterial competitors.

The researchers discovered that Agrobacterium tumefaciens’ T6SS injects toxins called Type VI DNase effectors (Tde), which then degrade the DNA of bacterial competitors. Once competitors have been killed, Agrobactrium tumefaciens reigns supreme and triggers plant disease. The bacterium also hosts an antidote to shield itself against its own attack.

The study also shows that Agrobacterium tumefaciens takes advantage of the host environment, which appears to enhance its weaponry and helps the bacterium to become a ‘superbug’ and gain an advantage over other competitors.

The scientists are keen to further explore how this weaponry operates, in the hope that they could manipulate the T6SS secretion system so that friendly bacteria could attack harmful bacteria. Alternatively, it may be possible to deactivate T6SS in particularly fierce bacteria to stop them gaining an advantage necessary for winning the bacterial warfare.

Professor Alain Filloux from the Department of Life Sciences at Imperial College London said: “We know that bacterial plant pathogens, such as Agrobacterium tumefaciens, trigger diseases in crops of tomato and bell pepper plants. Our research is a useful case study. Imagine that we could equip innocuous bacteria, which are beneficial for these crops, with a potent T6SS weaponry to kill harmful pathogens. This way we could develop new strategies to protect crops from bacterial infections and avoid economic loss.”

To test Agrobacterium tumefaciens’ bacterial warfare tactics, the researchers pitted the bacterium against various other bacteria. The results suggested that Agrobacterium tumefaciens gets ‘fitter’ once it is inside a host, where it receives an advantage for survival.

Within a petri dish, Agrobacterium tumefaciens was able to kill Escherichia coli (E. coli) by firing the Tde toxins. However, when it used the toxins against Pseudomonas aeruginosa, which is a very resistant bacterium that causes chronic lung infections in cystic fibrosis, this triggered a lethal counterattack and Agrobacterium tumefaciens did not survive.

When the bacterial duelling was tested inside a host - the tobacco crop Nicotiana benthamiana - Agrobacterium tumefaciens was able to attack Pseudomonas aeruginosa and ultimately gain a competitive advantage over this normally fierce and resistant plant and human pathogen. This new insight was only gained after the researchers investigated the bacterium in action in its own habitat.

Dr Abderrahman Hachani, also from the Department of Life Sciences at Imperial College London, explains why being inside an appropriate environment is so important for the bacterium’s survival: “What is really surprising about our results, and something we didn’t expect to find, is that Agrobacterium tumefaciens’s potency, or its ‘fitness’ and ability to outcompete other bacteria, is completely dependent on being within the plant. Imagine you are a deep sea diver, and you are in the metro with a scuba diving kit and a harpoon gun to defend yourself against a deadly attack. Not very useful, is it? The situation will be totally different if you are thrown in the sea, a more suited environment for your outfit. Once in the relevant context, your ‘fitness’ has improved, and you are much more capable to defend yourself, even if you come face to face with a shark.”

The scientists are keen to further explore how this bacterial weaponry operates in human bacterial pathogens in the hope that they could design new drugs to treat infectious diseases.

For example, Pseudomonas aeruginosa is a very resistant bacterium that causes chronic lung infections in cystic fibrosis (CF) patients. Scientists believe this bacterium uses T6SS to attack other competitors so that it is the only bacterium that persists as cystic fibrosis patients get older. Hijacking the T6SS system could potentially provide a new way of combating Pseudomonas aeruginosa lung infection in CF patients.

Professor Alain Filloux added: “The T6SS secretion system is found in lots of different bacteria that trigger many different infectious diseases, so it is crucial that we understand how it works. Our findings mean we will be able to work towards designing drugs that jam the T6SS gun and stop it from working. We could also find many other, as of yet undiscovered, toxins that might inactivate essential functions in bacteria. By understanding how bacteria harm each other, we will learn how to design new drugs that will mimic the activity of these new toxins.”

This research was funded by the Wellcome Trust, Medical Research Council and the Taiwan Initiative Research Cooperation.

REFERENCE: Lay-Sun Ma, Abderrahman Hachani, Jer-Sheng Lin, Alain Filloux, and Erh-Min Lai. ‘Agrobacterium tumefaciens Deploys a Superfamily of Type VI Secretion DNase Effectors as Weapons for Interbacterial Competition In Planta’. Cell Host and Microbe. July 2014. DOI: 10.1016/j.chom.2014.06.002