Social bacteria - an answer to the antibiotic arms race?

03 February 2017

Bacterial cells outnumber ours ten to one. We are on a cellular level 10% human. At the level of DNA, just 1% human. We can’t see bacterial cells because they are tiny. Indeed sperm cells, the smallest of human cells, are still more than 30 times larger than the average bacterial cell. In addition, no single species of bacteria actually outnumbers our cells. Until recently, this has led scientists to long dismiss our bacteria as irrelevant. But they are not mere freeloaders... 

It is now undisputed that the bacteria resident in our guts can influence a wide range of processes. They can modulate metabolism, alter behaviour and cause diseases. How can such small organisms, each functioning independently, have such measurable effects on a multicellular organism? This question has confounded scientists for years but now recent research suggests that the answer is shockingly similar: they don't. Instead, bacteria of the same species work together as a team, rather than individually, to manipulate their hosts. This illuminating discovery was made with the help ofVibrio fisheri, a species of bioluminescent - or glowing - bacterium.

Bonnie Bassler was a young microbiologist working on Vibrio fisheri when she noticed that they produced light only when they were grown in concentrated solutions. Fascinated as to why, she's since devoted her career to finding out. The bacteria, her experiments are showing, can exist in either of two behavioural states: one in which they carry out individual behaviours, and the other in which they carry out group behaviours.

The bioluminescent bacteria can transition between these two behavioural states by reading the concentration of ‘autoinducers’ in the solution. Autoinducers are simple chemicals, continuously produced by every single bacterium, which tell others “I’m here!” Every bacterium also listens to the autoinducers around them to calculate how many sister bacteria are nearby. And this is important because it's not enough to know just that there are other bacteria nearby, they also need to know their density or numbers. Group behaviours, like light production, typically fail unless a large number of individual bacteria participate together. Making light before it is useful is, at best, a waste of resources.

This process of making, sensing and responding to autoinducers is called ‘quorum sensing’. It was originally thought to have evolved in conjunction with the Hawaiian Bobtail Squid. The squid is a nocturnal hunter that stores the bacteria in pouches. By dilating and contracting these pouches, a squid can control the concentration of bacteria and thus whether V. fisheri produces light. On a cloudless night, when moonlight penetrates the water, this devious hunter contracts the sacs so the bacteria are concentrated and produce light at an intensity that exactly matches the intensity of the moonlight, masking the squid’s shadow. But when bioluminescence would reveal the squid, the sacs are dilated and most of their contents dumped, dimming the light and hiding the predator.

The elegant nature of the relationship between V. fisheri and the squid led many biomedical scientists to initially dismiss quorum sensing a trait unique to the then obscure glow-in-the-dark bacterium. It was considered irrelevant to the wider community because it was unclear how this knowledge would help fight human disease. This was a mistake. Bassler has shown that all studied bacterial species have quorum sensing communication systems that regulate group behaviours. In addition to bioluminescence, group behaviours include the production of disease causing agents, called ‘virulence factors’. Uniquely though, Vibrio cholerae, which causes cholera, stops making its virulence factors when the bacteria are in large dense groups.

The life cycle of V. cholerae is most likely responsible for its unusual quorum sensing. When not causing acute diarrhoea in people, V. cholerae lives harmlessly in the intestines of microscopic marine zooplankton called coccolithophores. Under these conditions it would be a waste of resources to make the cholera-causing toxin, so the bacteria have evolved not to make this virulence factor when they are in dense communities. But when cholera-contaminated water is consumed by humans, only a very small number of V. cholerae bacteria survive the gastric juices of the stomach and end up in the intestine. In these sparse conditions, V. cholerae has adapted to make a virulence factor that ultimately causes its host to have diarrhoea. This is clever exit strategy: the bacteria continuously make a pathogenic substance, which causes their host to continuously flush out their intestines, until they reach a density sufficient to successfully colonize a new body of water. At this time, V. cholerae switch to their group behaviour state, detaching from the intestinal wall and exiting the body through the diarrhoea set up earlier.

Understanding how bacterial communication relates to infectious disease has placed quorum sensing in the center of the biomedical map. Overcoming widespread antibiotic resistance is a major challenge facing the 21st century. A human gets infected with a bacterial strain and so undergoes an antibiotic treatment that kills the overwhelming majority of the bacterial cells. The person gets better. However not all the bacteria die - only those that lack a random genetic mutation making them immune to the antibiotic. The resistant bacteria persist and grow and the human gets sick again. Using a new antibiotic, the person is treated again and the same thing happens. We have unintentionally created ideal conditions for bacteria to evolve, and they are doing it at a faster rate than scientists can develop new antibiotics. These "superbugs" terrify doctors, and rightly so. If we cannot win this antibiotics arms race we risk forcing our society back to a time where patients die from treatable diseases. But here is where quorum sensing offers a ray of hope. Imagine if you could trick V. cholerae into thinking they are in a large, dense group. They would detach from the intestinal wall and harmlessly exit the human body… The principal of interfering with quorum sensing to stop virulence factor production can be applied to all infectious bacteria. What is most exciting about this approach is that it should not recapitulate the current ‘arms race’ conditions that force the bacteria to evolve. Quorum sensing may win us this war once and for all.

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