Instead of isolating antimicrobial agent-producing bacteria in laboratories, development is taking a new turn: Now the bacteria must live together just as they do in nature. That way we can get them to produce new antimicrobial agents.
They are out there—between blades of grass and under pine trees, in seawater, and down in the sediments of the seabed—the bacteria that can produce antimicrobial agents. We know this because their genes have been giving up this information through more than a decade of gene sequencing. However, bacteria with the potential is one thing—quite another is selecting the most suitable and having their genes activated so that they actually produce the substances. Most bacteria—in fact as much as 99 per cent—are quite reluctant to produce anti-microbial agents in the lab. These are the ones at the centre of Associate Professor Mikkel Bentzon-Tilia’s research project.
“When only about one per cent of the bacteria are immediately cultivable in the laboratory, there’s enormous potential in studying what it takes to make the other bacteria thrive. The aim of my project is to identify that potential. For decades we’ve been using soil bacteria to produce antimicrobial agents, but if we look at microbiology as a whole, the question is: where is it best to look for new organisms that can secure new antimicrobial agents? My project should also help to answer this question,” says Mikkel Bentzon-Tilia.
The associate professor works at DTU Bioengineering, where his research forms part of the overall exploration and understanding of bacteria taking place at the basic research centre Center for Microbial Secondary Metabolites (CeMiSt). In 2019, Mikkel Bentzon-Tilia received DKK 5.9 million from Independent Research Fund Denmark’s Sapere Aude programme to look for the promising bacteria.
Bacteria co-exist
Mikkel Bentzon-Tilia’s research is in line with a new bacteria approach emerging around the world: co-cultivation. This is when you grow the bacteria together instead of isolated in separate petri dishes, as the bacteria live together across species in large communities in the wild.
“The idea behind this new practice is that antimicrobial agent-producing bacteria come from entire ecosystems, and by mimicking their natural environment, we might be able to make them thrive in the lab so that they start producing antimicrobial agents,” says Mikkel Bentzon-Tilia.
"Our search for new antimicrobial agents never stops, but of course humans can make wiser use of these substances."
Professor Lone Gram
CeMiSt researchers already have results supporting this new approach, explains the head of the basic research center, Professor Lone Gram. “We’ve succeeded in getting sea bacteria to produce more antimicrobial agents by mimicking some of their living conditions out in the ocean—including what they grow on out there, what bacteria they live with, and what nutrients they feed on,” she says.
Mikkel Bentzon-Tilia’s project is therefore based on the whole community of microorganisms which are harvested directly from nature and taken into the laboratory for analysis. He is currently studying microbial communities from three environments— soil, seawater, and the seabed. The microbial communities have been carefully selected on the basis of gene sequencing that shows where the greatest potential is for the production of new antimicrobial agents.
“Initially, I look at the individual communities in their entirety. A microbial society is very diverse, potentially consisting of up to hundreds of thousands of different bacterial species. Of course, first and foremost it’s about studying the content of bacterial DNA that shows the production of antimicrobial agents. The DNA of the bacteria is interesting because it’s with good reason that they hold on to a very complex series of genes that enables them to produce antimicrobial agents. It costs energy for a bacterium to retain the genes—and bacteria are very energy-conscious. In other words, they don’t want to carry around genes that they can’t use for anything,” says Mikkel Bentzon-Tilia.
Bacteria living conditions studied
Part of the research is about measuring the physical and chemical conditions in the most interesting microbial communities.
“I study environmental parameters such as pH, nutrient salts, oxygen content, and carbon content, so that we get an idea of the natural living conditions of microorganisms. This helps us to become better at predicting in which natural environments we should look for anti antimicrobial agent-producing microorganisms,” says Mikkel Bentzon-Tilia, who hopes that his research can be the first step on the road to a ‘map’ that shows where we have the best chance of finding the microorganisms we need.
In addition, knowledge of the conditions of microbial societies in nature also allows researchers to imitate them in the laboratory and thus ‘turn on’ the microorganisms’ antimicrobial agent production.
Although the associate professor’s research may lead directly to some promising candidates that can be utilized for future antimicrobial agent production, the search for new organisms will continue—almost ad infinitum, predicts Lone Gram:
“It’s not humans who have invented resistance—it’s microbiology. After all, a bacterium that produces an antimicrobial agent must be resistant to this substance itself—or it will die. Resistance is an indispensable part of evolution because it is the microorganisms’ way of defending themselves when their existence is threatened by antimicrobial agents. Our search for new antimicrobial agents never stops, but of course humans can make wiser use of these substances, so we remain at the forefront of the ongoing evolution which is causing more and more resistant bacteria.”
Watch a short film about the search for novel antibiotics.