World news – Antibiotic resistance from random DNA sequences

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January 8, 2021

from Uppsala University

An important and still unanswered question is how new genes are created that cause antibiotic resistance. In a new study, Swedish and American researchers have shown how new genes that create resistance can arise from completely random DNA sequences. The results were published in the journal PLOS Genetics.

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Antibiotic resistance is a major global problem and the spread of resistant bacteria is causing disease and death and is a great cost to society. The most common way for bacteria to develop resistance is to pick up different types of resistance genes from other bacteria. These genes encode proteins (peptides) that can lead to resistance by: (i) deactivating the antibiotic, (ii) reducing its concentration, or (iii) changing the target of the antibiotic so that the antibiotic no longer adapts to it The target can bind and thus stop the growth of the bacterium. Once resistance genes have emerged, they can quickly spread between different pathogenic bacteria and reduce the effectiveness of our antibiotics. It is therefore important to identify and characterize new resistance genes as soon as possible in order to monitor the spread of resistance and to facilitate the treatment and development of new antibiotics.

To study the emergence of resistance genes, the researchers examined in Laboratory experiments to determine whether it is possible to generate a gene from random DNA sequences that would lead to antibiotic resistance. To this end, almost a billion random DNA sequences were first designed, which were then placed on a plasmid in the intestinal bacterium Escherichia coli. (Plasmids are DNA molecules that replicate independently of one another and can be transferred from one organism to another.)

These random DNA sequences were then expressed in the bacterium as short peptides. While most of these peptides had no effect on the bacterium at all, six different peptides did, causing the bacterium to become resistant to the antibiotic colistin, an important last resort antibiotic used in severe infections to kill the bacteria by binding to kill and destroy the cell membrane of the bacterium. These peptides caused resistance by increasing the expression of genes involved in modifying the bacterium’s cell membrane. This modification of the cell membrane meant that the antibiotic did not bind to the cell membrane and thus could not reduce the survival of the bacterium.

« We have now shown in two different studies that random sequences of amino acids can create new functions that beneficial to the bacterium, such as antibiotic resistance. This suggests that the development of new functions from random DNA sequences is not as unusual as previously thought, « says Dan I. Andersson, Professor of Medical Bacteriology and responsible for the Study.

« An important question that remains unanswered and requires further investigation is whether these new genes are naturally present in bacteria or can only be observed in laboratory experiments, » says Michael Knopp, postdoctoral fellow in the Department of Medical Biochemistry and Microbiology and the study first author.

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