A defense system has been discovered in Escherichia coli bacteria by Institut Pasteur scientists. In this system, the bacteria eliminate a small DNA molecule (the plasmid) known to carry antibiotic resistance genes, but not before the resistance genes have been integrated into the bacterial chromosome. In defending themselves, the bacteria establish antibiotic resistance. This discovery is a further step towards improving understanding of the spread of antibiotic resistance, a major public health challenge.
In May 2024, the World Health Organization (WHO) released its updated list of the main antibiotic-resistant bacteria. Carbapenem-resistant Enterobacterales are among those considered to be of critical priority. Carbapenems are antibiotics used as a last-resort treatment for infections. WHO believes that studying Enterobacterales will be crucial for the discovery of new antibiotics, as some produce an enzyme known as carbapenemase which makes them resistant to carbapenems. E. coli, the Enterobacterales species most often responsible for infections, was the focus of a study by a team from the Institut Pasteur.
The role of plasmids in E. coli resistance
Bacteria have their own DNA, carried by one or more chromosomes. They sometimes also have plasmids, mobile DNA molecules that can move between bacteria (both within the same species and between different species).
The genes that confer antibiotic resistance on bacteria are often found on plasmids.
The spread of plasmids, especially in E. coli bacteria, is therefore a major threat for public health.
If E. coli bacteria are not exposed to antibiotics for long periods, plasmids often become a burden for the bacteria, which end up losing them.
But unfortunately the resistance genes can move from the bacterial plasmid to the chromosome, where they are integrated in a stable way. This is what occurs in E. coli lineage ST38, which is often isolated from human infections and carries resistance genes in its chromosome. There are at least four ST38 clones disseminated in Europe that carry the OXA-48 gene inserted in the chromosome. The OXA-48 gene encodes the most frequently detected carbapenemase in France.
Elucidating the dissemination of carbapenem resistance genes
We were previously unaware of how antibiotic resistance genes were able to move from plasmids to establish themselves in the chromosome, despite the fact that this is a key step in the spread of carbapenem resistance.
In a new study, Philippe Glaser, Head of the Ecology and Evolution of Antibiotic Resistance Unit, and his team successfully integrated the OXA-48 gene into the chromosome of bacterial strains. "What made our study original was that we reproduced the phenomenon of gene integration in the laboratory, which was not an easy task. We used multiple environmental conditions and mutations to reveal the factors responsible for the gene's integration," explains Philippe Glaser.
Dieudonné Zongo and his PhD supervisor Isabelle Rosinski-Chupin identified the factors needed for the resistance gene to be integrated into the chromosome and then for plasmid loss to occur:
- The resistance gene must be carried by a mobile genetic element to enable capture by the chromosome.
- The plasmid must induce a fitness cost for the bacteria: the plasmid becomes a burden, making plasmid loss more likely.
- And, an entirely new finding: bacteria must produce proteins that cause them to eliminate the plasmid.
Discovery of an antiplasmid protein defense system
We knew that bacteria had defense systems protecting them from invasion by foreign DNA. Here, the research team revealed a system composed of two specific proteins (ApsA and ApsB) that can lead to plasmid loss in the host bacteria. "This is a defense system that destabilizes the plasmid," explains Isabelle Rosinski-Chupin. "This protein system also promotes the integration of resistance genes in the chromosome. The plasmid is eliminated slowly so that there is time for the OXA-48 gene to be integrated into the chromosome."
The scientists have therefore discovered a novel family of antiplasmid systems that plays a role in the circulation of carbapenem resistance genes.
An important discovery for antibiotic resistance research
"This discovery can help us understand the mechanism by which antibiotic resistance genes become established in bacterial chromosomes," adds Philippe Glaser. Bacteria that are integrated into a resistance gene in the chromosome in a stable way are more likely to spread worldwide and be resistant to antibiotics.
This study is part of the priority scientific area Antimicrobial Resistance of the Institut Pasteur's strategic plan for 2019-2023.
Source
An antiplasmid system drives antibiotic resistance gene integration in carbapenemase-producing Escherichia coli lineages, Nature communications, May 15, 2024
DOI: https://doi.org/10.1038/s41467-024-48219-y