Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Silencing bacteria

12.09.2017

HZI researchers pave the way for new agents that render hospital pathogens mute

Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a pathogen that elicits serious infections in humans and is resistant to a range of antibiotics. Researchers are therefore actively looking for targets for alternative agents that attenuate the bacteria.


Pseudomonas aeruginosa bacteria (left) often develop resistance to antibiotics and seek protection from external influences in biofilms.

HZI/Manfred Rohde


Crystal structure of the protein PqsA in complex with the intermediate Anthraniloyl-AMP (yellow), that is processed by PqsA.

HZI/Florian Witzgall

Pseudomonads can survive in so-called biofilms, which are dense constructs in which the individual bacteria are protected from the immune system and medications. In order to be able to produce a biofilm, the bacteria first have to communicate with each other by means of chemical signals.

Scientists from the Helmholtz Centre for Infection Research (HZI) in Braunschweig determined the three-dimensional structure of a protein that is involved in the production of the signalling molecules. Based on this structure, it is now possible to model perfectly fitting inhibitory substances that interrupt the signalling pathway to render the bacteria "mute". The scientists published their results in the international journal ChemBioChem.

In a way, bacteria do talk to each other. They do not communicate by words, but rather by chemical signals. This allows them, for example, to coordinate the penetration into a host or their proliferation. This special type of communication is called "quorum sensing".

The term, "quorum", originates from the time of the Roman Empire and corresponds to the smallest number of Senate members needed to win a vote. Pseudomonads use this system to trigger the production of biofilms, whereby the individual bacteria release signalling molecules and measure how many of their kind are in their vicinity at any given time. Once a threshold is exceeded, they commence their attack.

After the pseudomonads have aggregated into a biofilm, they are very difficult to eradicate – by the immune system or by medications alike, because even antibiotics are often ineffective against pathogens in biofilms. However, the bacterial communication system that contributes to the production of biofilm offers a suitable point of attack for alternative agents: These substances can suppress the communication, effectively making the bacteria remain accessible to the immune system and to antibiotics.

"Conventional antibiotics attack vital processes of the bacteria, which kills the bacteria and generates a selection pressure that forces the bacteria to develop resistance to the antibiotics," says Florian Witzgall, who is a doctoral student at the "Structure and Function of Proteins" department of the HZI directed by Prof Wulf Blankenfeldt. "But if an agent only attacks the communication of the bacteria, they stay alive and are only rendered harmless. Presumably, there is a lower pressure to develop resistance."

Bacteria utilise different systems to communicate with each other. Pseudomonas aeruginosa possesses three different communication systems, one of which is specific for this pathogen and is called pqs system (an acronym of Pseudomonas quinolone signal). Approximately ten percent of all genes of Pseudomonas aeruginosa are regulated by intercellular communication and this includes many genes that the bacteria need for infection of a host.

"The pqs system is an expedient target for medications, since it is fairly specific for Pseudomonas, it regulates a multitude of processes such as the production of virulence factors or biofilms, and there is no homologous system in humans," says Witzgall. The function of the pqs system is already known in much detail: In multiple steps, a number of proteins produce a signal molecule through which the bacteria communicate with each other and that regulates a multitude of genes, including the infection programme of Pseudomonas, through the activation of a DNA-binding receptor.

The HZI researchers recently looked at the first protein of this production chain and deciphered its three-dimensional structure. They used harmless Escherichia coli bacteria to produce the protein – called PqsA – in the laboratory and then isolated, purified and crystallised the protein. Especially the production of crystals is a protracted process, in the course of which the scientists tested more than 1000 different conditions to get to the desired result. Subsequently, they exposed these protein crystals to X-rays and recorded the diffraction patterns. They calculated the three-dimensional molecular structure of the protein from thousands of diffraction images. In all, the entire process took eight months to complete.

"Based on the elucidated structure, we now know where and how the PqsA protein binds to the starting substance for the later signal molecule," says Wulf Blankenfeldt. "This allows us to specifically design artificial molecules on the computer that firmly bind to PqsA and cannot detach again. This would block its function such that no signal molecules could be produced any longer." The result: The bacteria, lacking the signal molecule, would no longer be able to sense each other – they would basically be deaf and mute. The development of a molecule of this kind is now a task for active-substance research that can be based closely on the results of the structural biologists from the HZI.

The press release and a picture are also available on our website: https://www.helmholtz-hzi.de/en/news_events/news/view/article/complete/silencing...

Original publication:
Florian Witzgall, Wiebke Ewert, Wulf Blankenfeldt: Structures of the N-terminal domain of PqsA in complex with anthraniloyl- and 6-fluoroanthraniloyl-AMP: substrate activation in Pseudomonas Quinolone Signal (PQS) biosynthesis. ChemBioChem, 2017, DOI: 10.1002/cbic.201700374

Helmholtz Centre for Infection Research:
Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, are engaged in the study of different mechanisms of infection and of the body’s response to infection. Helping to improve the scientific community’s understanding of a given bacterium’s or virus’ pathogenicity is key to developing effective new treatments and vaccines. http://www.helmholtz-hzi.de/en

Contact:
Susanne Thiele, Press Officer
susanne.thiele@helmholtz-hzi.de
Dr Andreas Fischer, Editor
andreas.fischer@helmholtz-hzi.de

Helmholtz Centre for Infection Research
Press and Communications
Inhoffenstr. 7
D-38124 Braunschweig
Germany

Phone: +49 531 6181-1404

Susanne Thiele | Helmholtz-Zentrum für Infektionsforschung

More articles from Life Sciences:

nachricht How molecules teeter in a laser field
18.01.2019 | Forschungsverbund Berlin

nachricht Discovery of enhanced bone growth could lead to new treatments for osteoporosis
18.01.2019 | University of California - Los Angeles

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Ten-year anniversary of the Neumayer Station III

The scientific and political community alike stress the importance of German Antarctic research

Joint Press Release from the BMBF and AWI

The Antarctic is a frigid continent south of the Antarctic Circle, where researchers are the only inhabitants. Despite the hostile conditions, here the Alfred...

Im Focus: Ultra ultrasound to transform new tech

World first experiments on sensor that may revolutionise everything from medical devices to unmanned vehicles

The new sensor - capable of detecting vibrations of living cells - may revolutionise everything from medical devices to unmanned vehicles.

Im Focus: Flying Optical Cats for Quantum Communication

Dead and alive at the same time? Researchers at the Max Planck Institute of Quantum Optics have implemented Erwin Schrödinger’s paradoxical gedanken experiment employing an entangled atom-light state.

In 1935 Erwin Schrödinger formulated a thought experiment designed to capture the paradoxical nature of quantum physics. The crucial element of this gedanken...

Im Focus: Nanocellulose for novel implants: Ears from the 3D-printer

Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.

It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:

Im Focus: Elucidating the Atomic Mechanism of Superlubricity

The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.

One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Our digital society in 2040

16.01.2019 | Event News

11th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Aachen, 3-4 April 2019

14.01.2019 | Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

 
Latest News

Additive manufacturing reflects fundamental metallurgical principles to create materials

18.01.2019 | Materials Sciences

How molecules teeter in a laser field

18.01.2019 | Life Sciences

The cytoskeleton of neurons has been found to be involved in Alzheimer's disease

18.01.2019 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>