The World Health Organization (WHO) regards antimicrobial resistance, including antibiotic resistance, as one of the world’s major health challenges. A new fundamental understanding of antibiotic resistance could therefore potentially have a far-reaching impact on global public health, animal health, and the environment.
The traditional understanding of antibiotic resistance is that, based on a laboratory test, a bacterium is either susceptible to or resistant to specific antibiotics. This has been of crucial importance to how infections are diagnosed, patients are treated, and antibiotic resistance is monitored and controlled in humans, animals, food, and the environment worldwide.
However, we might need to set that understanding aside in the coming years, according to a group of researchers who, in a new opinion piece in the scientific journal ‘Trends in Microbiology’ , describe a possible paradigm shift in our understanding of antibiotic resistance.
Recent research from the DTU National Food Institute (links to articles below) has shown that antibiotic resistance depends on the context in which the resistant bacteria are found. Factors such as temperature, oxygen levels, and pH have a significant impact on whether a bacterium, even one carrying a resistance gene, behaves in a resistant manner or not.
The outline of a new picture is taking shape
This has been an eye-opener for the researchers, who believe that this new knowledge has the potential to turn many years of thinking about antibiotic resistance on its head, while also offering hope for far more effective ways to combat this global threat.
“We need to view antibiotic resistance as something that can change, depending on the shifting microenvironment in which bacteria move,” says Professor Frank Møller Aarestrup of the DTU National Food Institute, adding:
“This means that far more factors come into play. We need to find out what is required for a bacterium carrying a resistance gene to actually be resistant to antibiotics. Is it at a pH of 5 or 8, whereas we currently measure at a fixed pH of 7.2? What oxygen levels and temperatures are involved? Is the bacterium resistant if the patient has a fever or not? Is the bacterium in the gut, where there is no oxygen, or in the bloodstream, where oxygen is present?”
Current standard laboratory tests do not take into account whether the bacterium is in the gut or in the blood, or whether the patient has a fever or not, which are some of the biological conditions the bacterium encounters in the body.
“Resistance genes do not function in a vacuum. They are found in different bacteria and in varying microenvironments. We must therefore not only ask which resistance genes a bacterium possesses, but also when they actually make the bacterium resistant,” says Professor Thomas Bjarnsholt from the University of Copenhagen and Copenhagen University Hospital.
The researchers therefore suggest that greater attention should be paid to which specific resistance genes a bacterium possesses, and under what conditions the bacterium can cause disease.
“This makes it more difficult to measure in the laboratory, because we suddenly have to measure many different factors, whereas for many years we have gone to great lengths to standardise this type of measurement worldwide,” says Frank Møller Aarestrup.
New findings challenge established understanding
This new understanding may help to explain why a course of antibiotics sometimes fails to work, even though laboratory tests show that it ought to, or vice versa.
If resistance depends to a large extent on the bacteria’s environment, this also opens up the possibility of entirely new ways of thinking about combating antibiotic resistance.
“Now that it has been shown that a bacterium’s resistance depends on its environment, the next step will be for us to choose to use antibiotics that only lead to the development of resistance if certain specific conditions are met. This could, for example, be at a particularly high temperature that does not occur in humans. So we can start to consider entirely new strategies for combating antibiotic resistance in humans, animals, and the environment,” says Frank Møller Aarestrup.
The researchers therefore see opportunities for more targeted treatment of both humans and animals, but also a better chance of monitoring – and thus perhaps combating – resistance in the environment.
“The results lead us to believe that, in the future, we will be able to gain much better control over antibiotic resistance and thus, hopefully, take much more comprehensive action against one of the greatest health challenges of our time,” says Frank Møller Aarestrup.
New data collections and tests
This new knowledge challenges a fundamental assumption that has shaped resistance research for many decades, making it necessary to revisit and reassess large parts of the knowledge on antibiotic resistance that has been built up over many years of research. Therefore, large amounts of new data on resistance in relation to a range of biological conditions need to be collected.
“We need to start afresh and look at these genes in a new way to better understand resistance and, in particular, how it manifests itself under different conditions. If we can group resistance genes into categories, we can begin to use models and AI to identify the relationships between genes and varying conditions. This is a major undertaking that effectively restarts resistance gene research from square one,” says Frank Møller Aarestrup.
Facts about the article
The scientific opinion piece, originally titled ‘ From resistance genes to resistance states and enzymatic context-dependence in antimicrobial resistance,’ has been published in the scientific journal ‘Trends in Microbiology’.
This opinion piece is the result of a collaboration between the DTU National Food Institute, DTU Bioengineering, the University of Copenhagen, and Copenhagen University Hospital (KUH).
The following two studies form the basis of this opinion piece:
Trends in Microbiology
From resistance genes to resistance states and enzymatic context-dependence in antimicrobial resistance
16-Sep-2026
The authors declare no competing interests.