A group of researchers has analysed 1,240 wastewater samples from 351 cities in 111 different countries and found that bacterial latent antimicrobial resistance is widespread on all the world’s continents. The research was coordinated by the DTU National Food Institute in Denmark.
The antimicrobial resistance genes investigated do not currently pose a major risk, but some of them probably will in the future, according to the researchers, who on the basis of the study recommend enhanced surveillance of antimicrobial resistance in wastewater. The research has been published in the highly regarded scientific journal Nature Communications.
“The research shows that we have a latent reservoir of antimicrobial resistance that is far more widespread around the world than we had expected,” says researcher Hannah-Marie Martiny, who, together with Associate Professor Patrick Munk from DTU National Food Institute, is first author of the study.
The researchers compared the geographical distribution of antimicrobial resistance genes, both latent and already active (in the following referred to as acquired), and found a far wider geographical distribution of latent resistance genes than acquired ones.
“To curb future antimicrobial resistance, we believe that routine surveillance of antimicrobial resistance in wastewater, in addition to including already acquired resistance genes, should also encompass latent resistance genes, in order to account for tomorrow’s problems as well,” says Patrick Munk.
Consistent with previous investigations, the study shows that acquired resistance genes are present in higher amounts in sub-Saharan Africa, South Asia and the Middle East and North Africa (MENA) regions than in other parts of the world.
Hope of being able to curb a pandemic
It is natural for bacteria to have genes that can make them resistant to antibiotics, and such genes are found everywhere, for example in soil, water and humans. However, our use of antibiotics and other environmental pressures (see the section “Environmental pressures determine antimicrobial resistance” below) have driven resistance to spread to such an extent that the World Health Organization (WHO) has termed antimicrobial resistance (AMR) a pandemic.
When researchers around the world examine the scale and spread of the problem, they typically focus on resistance genes that are already able to jump between bacterial hosts. Acquired antibiotic resistance genes constitute a real challenge because they make treatment of humans and animals with antibiotics difficult or impossible.
Expanded surveillance would offer hope that researchers can determine where and how antimicrobial resistance arises and spreads and can map the ecology of the genes.
“By tracking both acquired and latent antimicrobial resistance genes, we can gain a broad overview of how they develop, change hosts and spread in our environment and thereby better target efforts against antimicrobial resistance (AMR). Wastewater is a practical and ethical way to monitor AMR because it aggregates waste from humans, animals and the immediate surroundings,” says Hannah-Marie Martiny.
The study also shows that, globally, there are more latent resistance genes spread across the world than acquired resistance genes. Only in sub-Saharan Africa are there equal numbers of each.
“In general, I don’t think we need to be too worried about most latent antimicrobial resistance genes, but I do believe that some of them will eventually cause problems, and we would like to know which ones; because with that knowledge we may be able to predict which bacteria in future can be stopped by which medicines,” says Hannah-Marie Martiny; a view shared by Patrick Munk.
“When new antibiotics are developed – a process that takes many years – bacteria may already have invented new ‘scissors’ capable of destroying them. If we can study both types of genes over time, we may be able to find out which of the latent genes become problematic resistance genes, how they arise and how they spread across geography and bacteria, and in that way lessen the burden of antimicrobial resistance,” says Patrick Munk.
Latent antibiotic resistance mapped using functional metagenomics
There are several ways to test whether genes confer resistance to antibiotics, both through AI-based predictions and laboratory experiments. However, there is a degree of uncertainty associated with computer predictions, which can also blur the interpretation of results.
Latent resistance genes are identified by extracting DNA from a sample and then testing random DNA fragments to see whether they can confer antimicrobial resistance. The method is called functional metagenomics and involves inserting DNA fragments into a harmless bacterium. The bacteria that survive must have received a piece of DNA that provides resistance. This does not necessarily mean that the DNA fragment can move between bacteria naturally in the environment.
The difference between latent resistance genes and acquired resistance genes is precisely that acquired resistance genes are known to be able to jump to new bacterial hosts, whereas latent resistance genes can jump to new bacterial hosts in the laboratory, but researchers do not yet know whether they will at some point be able to do so in the environment.
“Our concern is that some latent resistance genes will become acquired resistance genes and thus become able to jump to different bacterial hosts out in the environment. Especially because the research also shows that they are present in large numbers in so many places around the world. That is why we would like to see them included in surveillance,” says Patrick Munk.
To what extent latent resistance genes develop into problematic acquired resistance genes is something the researchers do not yet know. Broad surveillance of both latent and acquired resistance genes will help answer this question.
May prevent treatment of infectious diseases
The classic way in which society becomes aware of acquired resistance genes is through infectious diseases that cannot be treated with antibiotics because of resistance. At the DTU National Food Institute there is a large collection of resistance genes, which is used by doctors and researchers worldwide when they need to determine whether a bacterium is antimicrobial resistant.
In the present study, the occurrence of all the different resistance genes in the wastewater samples was quantified to determine their geographical and environmental distribution.
Environmental pressures determine antimicrobial resistance
The environment acts as the referee in a constant elimination race when it comes to resistant bacteria. When antibiotics are present, susceptible bacteria die first. The few bacteria that initially carry a resistance gene survive and multiply. The following factors in the environment affect, for example, which bacteria die and which survive:
- Residues of antibiotics in the environment (from hospitals, agriculture, wastewater) inhibit or kill susceptible bacteria and give resistant bacteria an advantage, enabling them to spread more easily.
- Disinfectants and biocides, under repeated or prolonged exposure, can select for bacteria that tolerate these agents. These bacteria often also carry genes that confer antimicrobial resistance.
