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How to prevent pathogens from developing antibiotic resistances

For bacteria, the environment is rather like a big market where they can give and receive new survival strategies if need be. A group of researchers led by Prof. Dr. Elisabeth Grohmann at the Freiburg University Medical Centre is investigating how microorganisms exchange antibiotic resistance genes. In a project involving two hospitals in Mexico City, the molecular biologists are also investigating whether pathogens, resistance genes and antibiotic residues enter the wastewater system and become part of the agricultural water cycle where they can potentially become a serious threat to human health.

Multiresistant pathogens are a serious threat in intensive care units. Virtually none of the clinically used antibiotics is still effective against such pathogens, which have evolved molecular mechanisms to evade any attack that the pharmaceutical industry can throw at them. And what’s more, they react to such attacks relatively quickly. This ability to adapt to attacks is known as lateral gene transfer. Bacteria can exchange genes with each other, which enables them to immediately transfer to other microorganisms any successful invention that bacterial cells come up with in their fight against antibiotics. “We are interested in how resistance genes are exchanged on the molecular level and finding out if it is possible to intervene,” said Prof. Dr. Elisabeth Grohmann from the Department of Infectious Diseases at the Freiburg University Medical Centre. “We are also investigating how such resistances spread in the environment.”

A protein complex mediates gene exchange

Enterococcus faecalis, a bacterium that frequently occurs in hospitals, seen under the electron microscope. © Janice Haney Carr/CDC/Pete Wardell/www.wikipedia.org

The exchange of genes between bacterial cells is in many cases mediated by the so-called type IV secretion system (T4SS). T4SS are big multiprotein complexes (made up of between 10 and 15 proteins) in the bacterial cell envelope that translocate DNA (a circular piece of DNA called plasmid with one or several genes) across the cell envelope. They do so through direct contact with each other. This process is known as conjugative plasmid transfer; the recipient cell integrates the plasmid, which is then transcribed, translated and transferred to daughter cells. Grohmann and her team are aiming to understand and reduce the dissemination of antibiotic resistance via conjugative T4SS and have already investigated some of the enzymes involved in this process in model organisms of the genera Enterococcus and Staphylococcus. In addition, they have access to substance databases which they can screen for substances that inhibit individual components of the bacterial T4 secretion system. “For clinical applications, we would like to find substances that inhibit the transfer of resistance genes,” said Rohmann who was born in the Austrian city of Graz.

Wastewater in Mexico City is transported through pipes into the Mezquital Valley where it either leaches into the soil, is used for the irrigation of crops or is recycled as drinking water. © Prof. Dr. Elisabeth Grohmann

Grohmann and her team are interested in finding ways to prevent the global spread of antibiotic resistances. Multiresistant pathogens or antibiotic residues from hospitals easily enter the environment, for example by way of the wastewater system, where the bacteria are able to swap the latest defense strategies. The bacteria return to humans, for example by way of drinking water or soil contamination. This is a particularly big problem in countries like Mexico that do not have sophisticated wastewater management systems. Grohmann is currently working with researchers from the University of Bonn and the University of Mexico City with the objective of monitoring the path taken by multiresistant pathogens and antibiotic residues from two big hospitals in Mexico City into the environment and back again.

From the intensive care unit into the drinking water system?

Mexico City’s wastewater is transported untreated into the Mezquital Valley around 70 km from the city where it leaches into the soil or is chlorinated and used as drinking water by local villages. Farmers use the wastewater to irrigate their fields; they sometimes tap into it from the channels before it has been treated with chlorine. The valley is a green oasis in the desert and the untreated wastewater is an excellent fertilizer. However, the groundwater in the area is also used as a drinking water reservoir for Mexico City and is transported back into the metropolis to supply private households, schools and kindergartens, as well as the two hospitals that are part of Grohmann’s investigations with drinking water.

“Do multiresistant pathogens or antibiotic residues from intensive care units enter the wastewater system and are therefore piped into the Mezquital Valley?” asks Grohmann. “And what happens to them in the Mezquital Valley soil?” A horrific picture emerges: in the intensive care units the pathogens learn how to survive antibiotic treatment. Equipped with this competence, they are transported through the wastewater system to the Mezquital Valley where they enter the soil. Grohmann and her team have used quantitative PCR to identify bacteria that are resistant to antibiotics in Mexico City’s wastewater system. However, the researchers have been able to show that the chlorine-treated water samples were either pathogen-free or only contained pathogens with no resistance genes, which led to the conclusion that the drinking water used by the villages is most likely clean.

Can genes also be swapped in space?

Legionella biofilm seen under the scanning electron microscope; the biofilm forms on a surface that was not treated with biofilm inhibitors. © Prof. Dr. Elisabeth Grohmann

The researchers are currently preparing a follow-up funding application in the hope that the DFG will provide them with the necessary funding for a project in which they want to have a closer look at what happens to the untreated wastewater in agricultural land in the Mezquital Valley. Are there multiresistant pathogens or antibiotic residues in corn or lettuce grown in the valley? The researchers also have the unique opportunity to use information relating to the temporal development of contamination in the Mezquital Valley: information dating back a hundred years or so tells the researchers how long the fields have been irrigated with wastewater from Mexico City. Some of the fields have only been irrigated with rainwater during this period. “We now plan to find out what the effects of long-term contamination are and identify differences with fields that have never been in contact with contaminated water,” said Grohmann.

Mexico City is not the most exotic place Grohmann and her team are involved in work to combat bacterial antibiotic resistance. In a cooperative project with the International Space Station (ISS), the researchers are investigating bacterial biofilms that develop on highly sensitive ISS components such as the exhaust air system. “Compared to free-living bacteria, the protective environment of biofilms provides the bacteria contained within them with increased resistance to antibiotics and/or disinfectants. In addition, biofilms greatly facilitate lateral gene transfer, which leads to a more stable biofilm,” Grohmann explained. This is why Grohmann and her team are focusing their laboratory investigations on substances that have the potential to prevent the formation of biofilms in tubes, the interior surfaces of the space station and on the surfaces of implants and prostheses. 

Further information:
Prof. Dr. Elisabeth Grohmann
Department of Infectious Disease
University of Freiburg
Hugstetter Straße 55

79106 Freiburg 

Tel: +49 (0)761/ 270 - 82 270

Fax: +49 (0)761/ 270 - 18 200

E-mail: elisabeth.grohmann(at)uniklinik-freiburg.de

Website address: https://www.biooekonomie-bw.de/en/articles/news/how-to-prevent-pathogens-from-developing-antibiotic-resistances