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Behaviour-changing signalling molecules as alternative to antibiotics

Bacteria display group behaviours when they form biofilms or cause infections. These group behaviours protect them against adverse environmental conditions. Thomas Böttcher from the University of Konstanz studies the signalling molecules that control this behaviour. His work involves identifying and characterising natural substances that can prevent bacteria from forming biofilms and from swarming. The substances’ medically relevant effect makes them a promising basis for new drugs in the fight against bacterial infections.

Dr. Thomas Böttcher is the head of the research group "Biological Chemistry" at the University of Konstanz that is funded under the DFG's Emmy Noether programme. © University of Konstanz

There are around ten times more bacteria than cells in and on the human body. These bacteria have important functions; amongst other things, they are indispensable for food digestion and defend the body against infection. Although bacteria usually live in peaceful coexistence with humans, they can seemingly suddenly exhibit pathogenicity and cause major diseases. The reasons for such behavioural change are often unknown.

“Bacteria have long been considered to be individual cells. However, there is increasing evidence that they naturally act as multicellular collectives. This enables them to engage in complex interactions and display coordinated group behaviour,” explains Dr. Thomas Böttcher, head of the "Biological Chemistry" work group that was established at the University of Konstanz in March 2014. Böttcher’s research is focused on how low molecular weight compounds modulate the coordination of bacterial population behaviour in the environment. In the presence of specific signalling molecules, bacteria are able to form three-dimensional networks on surfaces, so-called biofilms, which protect them against unfavourable environmental conditions. They can also form collectives in order to move about faster, glow in the presence of other cells or simultaneously produce toxins and secondary substances in order to coordinate an attack or their metabolism. “It is fascinating to see that organisms as simple as unicellular bacteria can display such complex behaviours, and that they can switch between life as individuals and a coordinated life in larger communities,” says Dr. Böttcher enthusiastically.

“Peer pressure” among bacteria

The behaviour of bacteria in larger collectives is controlled by a process known as quorum sensing, which, as the term suggests (Latin: quorum), relates to the number of certain signalling molecules that are present under certain conditions. The presence of a sufficiently large number of a specific species of bacteria in a particular environment leads to a rapid increase in the concentration of these signalling molecules. “When the concentration exceeds a certain threshold, a molecular switch is flicked, which results in the expression of certain genes,” says Dr. Böttcher. 

Depending on the situation, different genes can be switched on: genes that code for toxins, movement organs such as flagella or enzymes required for the formation or degradation of biofilms. The example of biofilms clearly shows how important this type of regulation is for bacterial populations. Biofilms are not beneficial in all situations. Although it is a physical barrier and gives the bacteria increased resistance to antibiotics, the biofilm matrix nevertheless strongly inhibits bacterial growth and substance exchange. Under certain circumstances, the bacteria produce signalling substances that lead to the degradation of the biofilms. The cells return to their free-floating planktonic life and are able to develop more successfully. However, such signalling molecules can also be produced by one organism in order to manipulate the behaviour of another. “There is a marine algal species that produces chemical compounds that are able to interfere with the quorum sensing system of bacteria and, amongst other things, inhibit the bacteria’s swarming motility,” says Dr. Böttcher, whose research is being funded by the DFG’s Emmy Noether programme.

The manipulation of behaviour as a competitive advantage

During his research stay in the USA, Thomas Böttcher isolated two bacterial strains from a red algae sample in which one inhibited the swarming1 of the other. Böttcher’s research showed that the bacterium Shewanella algae produces a previously unreported molecule that inhibits the bacterium Vibrio alginolyticus from swarming in its vicinity. “This molecule is a siderophore, an iron-binding compound used by bacteria for taking up iron from their environment. Biologically available iron is usually relatively limited and in great demand,” says Böttcher. Such siderophores can often be used not only by the bacteria that produce them, but also by other strains. However, the molecule, which the researchers named avaroferrin, binds iron in a way that prevents bacteria other than the producer from using it. “Avaroferrin therefore prevents V. alginolyticus from pirating iron and secures this essential resource for its producer,” explains Dr. Böttcher. Foreign organisms are thus cut off from the iron source and are unable to grow effectively. “Avaroferrin therefore has great potential as a biotechnological tool, for example for the treatment of bacterial infections,” says Böttcher.

Natural substance research with huge application potential

Dr. Thomas Böttcher uses an interdisciplinary approach to study the effect of signalling molecules on the coordinated behaviour of bacteria. © University of Konstanz

At the University of Konstanz, Thomas Böttcher is now specifically focused on identifying and studying natural substances that inhibit behaviour-relevant enzymes and hence modulate bacterial behaviour. “Although a wide range of proteins, whose crucial role in changing the behaviour of bacterial populations has been confirmed by genetic studies, are known, small molecule inhibitors for these proteins remain to be discovered,” says Böttcher. In order to be able to specifically identify new inhibitors among the large number of known natural substances, the target proteins are labelled with chemical probes and used to analyse metabolites and natural substances extracted from a diverse range of organisms. “The probes tell us whether a new inhibitor is present in a complex mixture. We can then purify the compound and determine its structure,” says Böttcher. When a new inhibitor is identified, the researchers subsequently characterise it and study its mechanism of action in detail. 

The new “Biological Chemistry” work group has already commenced some projects. “We are currently working on clarifying the structure of a potential new antibiotic and are carrying out studies to elucidate the modulation of bacterial behaviour,” says Böttcher. The research group is also focused on research into the cooperative behaviours and biofilm formation of bacteria and ways to manipulate these behaviours which, although very different, also play a key role in infectious diseases. 

Dr. Böttcher’s research group is in good hands with these particular research topics at the University of Konstanz. “Chemistry and biology are closely linked and the Graduate School Chemical Biology was another decisive reason for me to come to Konstanz,” says Böttcher. Since Böttcher’s research also deals with natural substances with medically relevant effects, he is also interested in working with industry. “The ideal scenario would of course be if we were able to transfer a promising concept into practice and make it suitable for human application, for example for the detection, prevention and treatment of infectious diseases,” says Böttcher looking at future prospects.

1Swarming: Swarming bacteria move over surfaces as collectives, thereby forming complex movement patterns such as whirls and jets. These structures develop as a result of interactions between chemical factors that inhibit or promote collective motion.


Further information:
Dr. Thomas Böttcher
Department of Chemistry
University of Konstanz
E-mail: thomas.boettcher(at)uni-konstanz.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/behaviour-changing-signalling-molecules-as-alternative-to-antibiotics