Opinion: interrupting how bacteria communicates could scupper infection and slow down the development of bacterial resistance

By Aobha Hickey, Jerry Reen, Fergal O'Gara and Gerard McGlacken, UCC

Communication is the very foundation upon which our society is built. From how we form connections, to the spread of knowledge and international relations, we adopt assorted dialects even within the scope of our own languages. We also know that humans are not alone in our need to communicate. Group hunters like lions and wolves coordinate their attacks through different cues and signals. Their potential prey can equally employ auditory warning signals to alert other vulnerable creatures to the imminent danger. The languages used between these various animals are studied and reported in depth. 

But what about tiny organisms like bacteria – how do they communicate? Bacteria are tiny, single-cell microorganisms, about 1,000 times smaller than the tip of a pencil. They can inhabit virtually any ecosystem on the planet and can survive in the most extreme conditions, even space.

They live on and around us and are generally not harmful. The quantity of bacteria on and in our bodies is so great that we have more bacterial genes than human ones. They mostly aid digestion in the gut, but also help prevent infection in the nose and mouth. These microbes are the good guys but, as is the case with most stories, some bacteria fall into the bad guys category. Some common illnesses caused by harmful bacteria include urinary tract infections and food poisoning.

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Estimated to have appeared nearly four billion years ago, bacteria are the ancestors to nearly every plant and animal on our planet. During their extended stay, some of these archaic beings have developed the ability to communicate with one-another and co-ordinate their activities. In fact, multiple bacteria can work together to accomplish tasks that would be non-productive for a single bacterium.

One of the most intriguing cooperative behaviours is bioluminescence (the release of light). This form of co-operation was first discovered in the 1970s through the study of a marine bacteria called Aliivibrio fischeriThese bacteria adopt a remarkable relationship with the Hawaiian bobtail squid Euprymna scolopes.

Each day at dusk, the squid attracts the bacteria into its light organ where the bacteria receive sustenance and shelter, and happily multiply. When the bacterial colony becomes sufficiently large, bioluminescence is initiated. The brightness of the light emitted from the organ is controlled by the squid in response to the light of the moon. As a result, the squid does not cast a shadow on the seabed, effectively camouflaging itself from its predators at night. Millions of bacteria emit light in unison, creating camouflage that is conceivably more effective than light from a single, microscopic cell.

From US National Science Foundation, the powerful and mysterious relationship between the Hawaiian bobtail squid and its resident bacteria

But how do the bacteria know when to co-ordinate this behaviour? The language used by many bacteria consists of small chemical signals, or molecules, instead of words. A bacterium makes the small molecule and releases it into its environment, as a way of saying "I’m here and we need to do X, Y or Z" to other bacteria.

Other bacteria in the colony ‘listen out’ for the signals while also releasing their own. The denser the population becomes, the louder the signal. Once the signal reaches a certain level, the bacteria alter their actions to behave as a multicellular unit and execute the coordinated action.

Bacteria use this communicative network to perform all sorts of auspicious tasks like cell multiplication, motility and the production of various proteins. They use chemical communication to coordinate their behaviour to survive, often to the detriment of the host, which is sometimes us humans.

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One such example is the bacteria Pseudomonas aeruginosa which infects the lungs of immunocompromised patients, particularly those with Cystic fibrosis. In this case, bacteria communicate with each other to create a protective biofilm which covers the entire population of bacteria. This group behaviour is a major problem in the clinical treatment of pseudomonas infections. The protective layer in which biofilms are encased is very difficult to penetrate, making the infection increasingly challenging to treat using traditional antibiotics, effectually promoting antibiotic resistance.

The emergence of resistant species has led researchers to return to the drawing board in an effort to discern new therapeutic routes. If bacteria communicate to protect themselves against our immune system and antibiotics, could we interrupt this social network as a new route to tackle infection? By making small molecules similar to those produced natively, we could confuse the bacteria. Research has been promising, as Pseudomonas aeruginosa struggles to create the proper biofilm architecture when chemical ‘words’ are introduced to their environment.

What is unusual and counterintuitive about interrupting bacterial communication is that we interfere with their disease-causing attributes without killing the bacterial cells. So why is this a good thing? Well think about how bacteria become resistant to antibiotics. Antibiotic resistance occurs when a bacterial cell replicates and one of the offspring experiences a random genetic change (or mutation). By chance, this new genetic coding allows the offspring to be less susceptible to antibiotics. This bacterium thus survives antibiotic treatment and passes its favourable genes onto the next generation. The prevailing survival of the mutant is dependent on the destruction of the others. If we do not kill the colony, then the mutant has no genetic advantage.

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Research in UCC is bringing together the collaborative expertise of microbiologists and synthetic chemists to understand the complex networks employed by bacteria and design new molecules to disrupt their group behaviours. Some signalling molecules of certain species are known, but others need to be discovered. Current experiments work with millions of bacteria at a time, introducing novel small chemical alterations, so that the bacteria struggle to communicate and work in unison. For Pseudomonas, this means no protective biofilm, allowing for more successful treatment in combination with antibiotics.

However, it can get a little more complicated. We have shown that communication can transpire between different species of bacteria and even fungi. Many of these pathogens co-inhabit natural ecosystems and a variety of microbes can also live within an infected site. This can often cause a more severe illness, that demands a unique therapeutic approach.

Our research continues to try and learn the language of bacteria and study the communicative pathways they use to perform tasks which benefit their colony. We synthesise confusing words in an attempt to prevent bacteria from enacting cooperative behaviour both within and outside of their own colonies. Overall, this approach could scupper bacterial infection and slow down the development of bacterial resistance.

Aobha Hickey is a PhD researcher with the School of Chemistry at UCC. She is an Irish Research Council awardee. Dr Jerry Reen is a Lecturer in Molecular Microbial Ecology in the School of Microbiology at UCC and funded through the Health Research Board. Professor Fergal O'Gara is Professor Emeritus of Microbiology at UCC and a funded investigator with SSPC, the SFI Research Centre for Pharmaceuticals. He is a former Irish Research Council awardee. Dr Gerard McGlacken is a Senior Lecturer at UCC and funded through SSPC.

The views expressed here are those of the author and do not represent or reflect the views of RTÉ