Resistance to antibiotics leads to nearly one million deaths worldwide each year. Combating that resistance is naturally a global health priority. Scientists from the University of Fribourg, with help from colleagues in Bern and Rennes, have discovered that specific genes in certain bacteria not only strengthen their resistance to treatments but make them more dangerous as well. Their research has been published in mBio, the flagship journal of the American Society of Microbiology.

“Antimicrobial resistance is outpacing advances in modern medicine, threatening the health of families worldwide,” the WHO Director General Dr. Tedros Adhanom Ghebreyesus declared unequivocally in a report published last October by the UN agency. According to the report, between 2018 and 2023, “antibiotic resistance rose in over 40% of the pathogen-antibiotic combinations monitored.” Simply put, in nearly half the cases studied, bacteria became more resistant to treatments. This dramatic trend led to nearly one million direct deaths each year around the world.

Understanding antibiotic resistance mechanisms
It comes as no surprise then that the fight against antibiotic resistance is both a global health priority and one of the missions of the Swiss National Reference Center for Emerging Antibiotic Resistance (NARA), located at the University of Fribourg. As the NARA Director Dr. Laurent Poirel explained, “Bacteria that we have managed to combat easily until now with antibiotics are now increasingly developing resistance. Our role is to understand what the mechanisms are that completely undermine the efficacy of the treatments and come up with solutions so that medicine does not face a terrible regression.”

In the present study, researchers wanted to know if specific resistance genes that code for so-called AmpC enzymes could affect bacteria’s capacity to multiply and spread, that is, affect their pathogenicity, their ability to cause disease. The experiments were carried out using E. coli, the most frequent pathogen in humans, as a model organism. It has also been known for several decades that AmpC enzyme acquisition is extremely common in E. coli and that those enzymes provide the bacterium with resistance to cephalosporins, a class of antibiotics used to treat many bacterial infections.

Genes above reproach
E. coli acquires the ampC gene when a plasmid (a small circular DNA molecule that is mobile and can carry genes) transmits the gene to the bacterium. Once this gene is integrated, the bacterium becomes resistant to many penicillins and cephalosporins, which are used as first-line treatments. For years, however, the scientific community thought that the acquisition of such resistance genes was either neutral or even disadvantageous to their host in terms of the energy expended. Indeed, the inherent “cost” to the bacterium is usually associated with the production of the plasmids carrying the resistance genes which are significant consumers of energy. However, Dr. Poirel and his colleagues have something like bad news to deliver. They have discovered that, contrary to earlier thinking, these genes are able to make the bacterium even more pathogenic.

Bacterial fitness
The scientists were greatly surprised when they managed to demonstrate that these genes act on the physiology of the bacterium. They do so in the following way.
First of all, the researchers showed in vitro that E. coli’s acquisition of plasmids carrying several ampC genes did indeed have a cost in energy expenditure. The bacterium offset that expenditure by producing fewer flagella, the tiny “propellers” that serve as the indispensable motors of bacterial mobility. This resulted in the bacterium conserving energy and growing faster in the lab under culture conditions, where it is allowed to multiply while being shaken (classic experimental conditions that allow for better oxygenation).
However, this negative autoregulation was not observed when the bacterium produced certain enzymes belonging to this AmpC family. Rather, flagella production, which is supposed to diminish, was “boosted” by the presence of the AmpC enzyme in question.
By conducting in vivo experiments, the researchers were thus able to confirm that certain very commonplace versions of AmpC do bring about the production of bacterial flagella, rendering the bacterium both more mobile and more pathogenic in a living organism and therefore quite possibly in the human body as well.
This discovery shows that certain resistance genes not only provoke the destruction of the antibiotic that is supposed to kill the bacterium, but they also transform the bacterium’s pathogenicity by giving it an enhanced capacity to multiply and spread within the site of the infection.
This represents a new paradigm, according to Dr. Poirel and his colleague Dr Otavio Raro, who was very much involved in the study, “We have discovered that certain very specific and unfortunately very widespread genes don’t merely help the bacteria to survive the antibiotics, they render them even more pathogenic by increasing their ability to cause infections!”
These results pave the way for extending new research to many other genes that are resistant to antibiotics. The aim would be to identify those that have, or do not have, an impact on resistance as well as pathogenicity. This would make it possible to better target these mechanisms with existing or future treatments, and ultimately to reduce the pathogenicity of the bacteria that are implicated.