The Seesaw Effect Of Bacterial Antibiotic Resistance

05/30/2016 11:30 EDT | Updated 05/31/2017 05:12 EDT
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Multi-drug-resistant bacterium. Antibiotic sensitivity test. The bacterium is not sensitive to the tested antibiotics.

A few months ago, the discovery of the antibiotic resistance gene mcr-1 sent shockwaves through the public and the health communities. This piece of bacterial DNA, also known as plasmid-mediated colistin resistance, revealed bacteria had developed a mechanism to tolerate yet another antibiotic. While this milestone marked another nail in the coffin for antibiotics, the true concern had to do with another troublesome feat of resistance.

Bacteria have long known to be able to work together to keep themselves safe from a variety of antibiotics. The most common route is through the transfer of genetic material, such as mcr-1, from one bacterium to another. This concept is known as horizontal gene transfer (HGT).

HGT has become a major player in resistance as it seemingly can occur anywhere. Usually, the action happens within environmental microbial communities regardless of species type. More worrisome, the same process can occur in each and every one of us inside our intestines.

In the microbial world, different species sense changes in the environment and then work together as a team to weather the storm.

In the case of mcr-1, HGT has been seen suggesting bacteria carrying this gene and others may be able to resist several antibiotics. Last week, this was realized in the United States with the discovery of a bacterium possessing mcr-1 and other resistance genes. However in this case and in most others, the bacteria can still be killed with other antibiotics. They may be multi-drug resistant strains but are not the truly feared pan-resistant isolates.

While this may make some breathe easier, there is another complication. Although bacteria with mcr-1 may not be able to resist all antibiotics as a result of HGT, they may still survive medical treatment. They accomplish this is by mingling with other bacteria carrying different types of antibiotic resistant genes. In times of stress, the neighbours co-operate with each other to deal with the pharmaceutical intervention.

Co-operation is a standard part of nature and has been observed in a variety of ecological communities. In the microbial world, different species sense changes in the environment and then work together as a team to weather the storm. The methods behind this phenomenon have been examined and to some extent understood. However, in the case of mutual antibiotic resistance, the mechanism has been rather elusive.

Now that lack of knowledge may change. Last week, a team of American researchers revealed how bacteria work together to resist an antibiotic challenge. Based on their results, species can give and take such that both groups use a seesaw effect to survive and thrive.

The group focused on the bacterium, Escherichia coli. In the lab, they separated the bacteria into two groups. Each was then given the ability to resist an antibiotic. One gained penicillin resistance while the other resisted against chloramphenicol, which is widely used as a preservative.

The two groups were mixed together in a tube and then subjected to regular doses of both antibiotics, much like what happens in the real world. Over several days, the researchers attempted to isolate and count the different types of bacteria. If there was co-operation, both would survive. However, if the two different bacterial types didn't get along, both would be doomed.

When the results came back, the researchers realized there was a third option. Over the course of the dosing period, the different types of bacteria seemed to grow in waves similar to the action of a seesaw. Initially, those resistant to chloramphenicol grew well while the penicillin-resistant microbes stayed consistent. Then, after three days, the tables were turned. The penicillin-resistant bacteria grew incredibly well while the other type waned. The cycle repeated itself every three days for two weeks.

With this odd observation in hand, the team wanted to learn if this give and take was due to communication or due to the actual method of antibiotic intervention. To accomplish this, the team provided a constant stream of antibiotics instead of regular dosing. When this happened, the situation changed dramatically. Instead of give and take, the bacteria grew almost at the same pace. The researchers had achieved a stable mutualism between the groups.

There was one more question left unanswered. The group wanted to know what would happen if HGT occurred and a double-resistant version emerged. When they attempted this by adding a bacterium with both resistance genes, the oscillations stopped. The double-resistor then gradually took over the system and eventually wiped out one of the groups.

The results offer an interesting perspective to those looking to combat antibiotic-resistant infections. If oscillations occur in the same manner, certain populations may be detected and targeted as their turn to grow comes. This may allow for faster diagnosis and decision-making on alternative antibiotic treatment. In addition, detection of multiple resistant strains may be made easier as they will dominate any population.

The results also highlight the risks of constant dosing in the formation of mutualistic communities. Although this may not be a concern in human medicine, in agriculture, this concept occurs quite often as antibiotics are introduced through food and water supplies. Consistent exposure in animals may make the bacteria inside an animal even more resilient. The end result may be stronger resistance through mutualism and wider spread as seen in mcr-1 and a number of other resistance genes.

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