"Selfishness" survives antibiotic resistance

Antibiotic resistance is increasing worldwide and is already causing thousands of deaths each year. Until then, it was assumed that some selection pressure was needed for the permanent preservation of resistance genes. Now, a Kiel research team has shown that bacteria can maintain antibiotic resistance even without selection pressure. Even the occasional administration of antibiotics leads to this latent antibiotic resistance, so that all subsequent generations of bacteria are 100% resistant to the drug.

Kiel – Part of the genetic information of many microorganisms is present on what are called plasmids. These are genetic elements that consist solely of a ring of DNA and can grow independently. Most bacteria have such plasmids because they allow them to acquire new genetic information. This is done by the so-called horizontal gene transfer: in this process, the plasmids provide the bacterial cells with new genetic material, even beyond the borders of other bacterial species. This allows bacteria to adapt quickly and flexibly to changing environmental conditions, which is particularly beneficial for pathogenic bacteria.

However, the plasmids are not "free" for the host organism because they use host cell resources, e.g. for energy supply or reproduction. Until now, scientists have assumed that plasmids are only hosted by bacteria to the extent that they can provide an evolutionary advantage.

A team of researchers from the Institute of General Microbiology of the Albrechts-Kiel Christian University (CAU) has now demonstrated, in collaboration with colleagues at the Ben Gurion's Negri Is not always the case: use the model organism Escherichia coli as an example. for example Commonly found in the intestines of various vertebrate bacteria, scientists have been able to demonstrate, as part of a research work conducted by the Kiel Evolution Center (KEC), that plasmids can persist permanently in bacteria , without the host deriving a tangible benefit from it. However, in the long run, they preserve the potential for rapid and evolving adjustments under changing environmental conditions.

How to survive plasmids without selection pressure

Normally, the so-called positive selection pressure ensures that certain advantageous functions of the plasmid prevail for the host. Such external fitting pressure would be for example the gift of an antibiotic. Here, the bacterium takes advantage of the resistance genes contained in the plasmids and can use them to develop insensitivity to the antibacterial agent. Until now, it has been assumed that the plasmids also constituted a charge for the bacterial cell and were thus present only as long as they were necessary. If the bacteria are no longer exposed to antibiotics and thus suppress the selection pressure, the plasmids must theoretically be lost slowly and disappear.

Since various plasmids are present in large numbers in the wild all over the world, this hypothesis can not be true. To find out what's really happening with plasmids without selection – that's to say antibiotics – Kiel researchers have conducted an evolutionary experiment. For this, they have observed the bacterium Escherichia coli for a total of 1000 generations. They studied the behavior of a particular plasmid, still poorly studied but present in many bacterial hosts, in the absence of such a selection pressure – so that the host can not derive no functional benefit from its existence.

Environmental conditions also require the survival of antibiotic resistance

"Our research shows that if the incidence of non-antibiotic plasmids decreases, they can survive at a low and stable level," said Tanita Wein, PhD student at the working group of the genomic microbiology working group at CAU and author Main of the study. "With these discoveries, we are providing a new evolutionary explanatory approach to the ubiquitous presence of plasmids in nature," continues Wein.

New class of antibiotics studied

5:06:19 – The fight against multidrug-resistant bacteria is becoming more difficult, year after year, with the decrease in the range of antibiotics still used. The new active ingredients are therefore in great demand. Researchers at the University of Tübingen have studied a promising new class of antibiotics and discovered the mechanism by which these active substances destroy bacteria. read

To further study the influence of environmental conditions on the persistence of plasmids, the researchers compared the effects of different ambient temperatures: on the one hand, the optimal temperature for the growth of the host bacterium at 37 ° Celsius, on the other hand, conditions inducing stress of only 20 ° Celsius. The results of the experiment showed that at cold temperature, the frequency of the plasmid decreased more slowly than in the temperature range preferred by the bacteria.

The persistence of plasmids in bacteria therefore does not only depend on the positive selection of certain functions, but is also strongly influenced by environmental conditions. "We have been able to show that the unfavorable conditions for the bacterium can be beneficial for plasmid survival because they can then reproduce more efficiently," says microbiologist Wein. The persistence of plasmids is therefore probably an intrinsically controlled process and not necessarily associated with a benefit to the whole organism, explains Wein.

The laboratory file "Antibiotic resistance"
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The administration of an antibiotic at one time is enough to develop 100% resistance.

Some authors of the new research: Prof. Tal Dagan (left), Tanita Wein and Dr. med. Nils Hülter from the Institute of General Microbiology of the UAH

Some authors of the new research: Prof. Tal Dagan (left), Tanita Wein and Dr. med. Nils Hülter from the Institute of General Microbiology of the UAH
(Image: © Institute of General Microbiology, CAU)

Another important aspect was discovered by Kiel researchers, who were also supported by the DFG Priority Program (SPP) 1819 "Rapid Evolutionary Adaptation" priority program, when they exposed the bacteria to a antibiotic without selection pressure after the experiment. In addition, the single dose results in 100% drug resistance for all subsequent generations of bacteria. In this case, there is talk of an "evolutionary bottleneck" through which, figuratively, only insensitive individuals pass.

Thus, new research shows that stable persistence of plasmids during evolution can lead to the fact that the antibiotic resistance of a bacterium remains latent, even though it is not yet come into contact with the active ingredients. "Our findings on the example of Escherichia coli thus offer promising research approaches to better understand the role of plasmids in the rapid adaptation of different bacteria to changing environmental conditions," says Prof. Tal Dagan, KEC member and head of the genomic microbiology working group. together.

Original publication: Tanita Wein, Nils F. Hülter, Mizrahi Itzhak, Dagan Valley (2019): the emergence of plasmid stability under nonselective conditions maintains antibiotic resistance; Nature communications, Published June 13, 2019 https://doi.org/10.1038/s41467-019-10600-7

C. Urban: Christian-Albrechts University of Kiel, 24118 Kiel