Keeping bacteria quiet

A recurring problem in medicine is bacteria’s tendency to evolve resistance to antibiotics. A professor of biological engineering, MIT’s Timothy Lu, recently said somewhat gloomily that, “it will be very hard to make evolution-proof therapy, there is just too much pressure for the bacteria to survive.”

But the trickle of results from a new line of research, which takes a novel approach to treating infection, suggests there could be another way to keep bacteria at bay.

Traditional antibiotics target infections by killing or preventing the growth of bacterial cells. But bacteria frequently evolve resistance to treatments, due to their unusual (and pretty awesome) ability to transfer genes between themselves via thin cytoplasmic tubes. However, a new class of drugs in development tries to get around this problem – instead of targeting bacteria cells’ growth directly, these drugs target the mechanism that bacteria use to communicate with each other.

Bacteria, it turns out, are quite chatty. Some communicate almost all the time, by releasing chemicals into the environment around them that other bacteria can sense – whether the environment is the soil, a test tube or your stomach. When in a crowd, many bacteria will also begin releasing harmful chemicals, called toxins. In many infections it’s these toxins that cause the symptoms of disease.

At the moment, most therapies try either to reduce the production of these toxins directly, or to kill the bacteria off altogether. But the major stumbling block with these sorts of approaches comes down to the same process that’s helped to keep us all alive so far: evolution. If just one cell line evolves a mutation that confers resistance to a particular drug, the gene(s) conveying that resistance can spread rapidly through what’s called ‘horizontal transfer’, where bacterial cells share genes among themselves.

It has been clear for some time that bacteria’s capacity for rapid evolution is a time bomb for medical care. In April 2014, the WHO called the problem of antibiotic resistance ‘a major threat to public health’, and the pressure to find a global solution is greater than ever.

One intriguing approach, beginning to show promise in the lab, aims not to harm the bacteria themselves, but to prevent them from talking to each other.

Bacteria know how many bacterial cells are around them by measuring the concentrations of specific chemicals they secrete into their environments. These concentrations are detected through a process known as ‘quorum-sensing’, and affect the behaviour of sociable bacteria in a variety of ways.

Some bacteria, for example, use quorum-sensing chemicals as triggers for the production of nutrient-collecting compounds. Others regulate the production of bio-luminescent proteins depending on their company. And some use quorum-sensing to control the secretion of the toxins that cause disease.

With this behaviour in mind, a new class of drugs has been proposed, using proteins called ‘quorum-inhibitors’ to disrupt bacteria’s sensing mechanisms and trick them into thinking they’re alone.

A proof-of-concept study from researchers at the University of Wisconsin, published last August, showed that bacteria with disrupted quorum-sensing mechanisms failed to re-evolve quorum-sensing, even in the presence of healthy bacteria. In other words, this treatment might, just might, be evolution proof.

Although the mechanism is not fully understood – the authors suggest that below a certain threshold, communicating bacteria are ignored or over-ruled by the insensitive bacteria – their results suggest that these alternative, communication-focused method may one day become a viable alternative to current antibiotic treatments.

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