Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Complementing conventional antibiotics

24.05.2018

Frankfurt scientists reveal atomic details for one of Legionella’s enzymatic weapons and develop first inhibitor

Antimicrobial resistance (AMR) is a major medical problem worldwide, impacting both human health and economic well-being.


3D structure of the enzymatic active part of SdeA toxin

Nature/Kalayil et al, Mai 2018

A new strategy for fighting bacteria has now been reported in the latest online issue of Nature by a research group headed by Prof. Ivan Dikic at the Goethe University Frankfurt. The scientists revealed the molecular action mechanism of a Legionella toxin and developed a first inhibitor.

As resistance continues to spread, common infections such as pneumonia and salmonellosis are becoming increasingly harder to treat. Two factors drive the AMR crisis: human negligence in the use of antibiotics and a lack of truly novel antibiotics for more than 30 years. According to a recent report by the World Bank, by 2050, AMR may reduce the global gross domestic product by 1.1% to 3.8%, depending on which scenario plays out.

Scientific efforts are underway to achieve better control of microbial infections. One promising approach is to limit damage to host cells and tissues in the course of a bacterial infection by blocking the microbial processes that cause such damage. The laboratory of Ivan Dikic, Director of the Institute of Biochemistry II at Goethe University, has been working in this field for the past decade. As Dikic explains:

“We believe we can find new treatments that complement conventional antibiotics by targeting specific groups of bacterial effectors with rationally designed drugs. In this way pathogenic damage can be decreased, which helps patients better tolerate bacterial infection. This is a relatively new field that is attracting more and more attention in the community.”

To prove that this strategy is a viable option for tackling bacteria, Dikic’s team studies Legionella, which are known to cause pneumonia and are especially dangerous for immunocompromised patients. Recently, the Frankfurt scientists were involved in identifying a novel enzymatic mechanism that Legionella bacteria use to seize control over their host cells. Dr. Sagar Bhogaraju, who works at Goethe University’s Buchmann Institute for Molecular Life Sciences as part of the Dikic team, reports: “We showed that Legionella enzyme SdeA acts as a toxic bacterial effector. It promotes the spreading of bacteria by targeting the ubiquitin system, one of the cell’s powerful protection mechanisms against stress.”

Ivan Dikic’s group has now reported a further breakthrough in the journal Nature: they succeeded in solving the atomic structure of SdeA. “The enzyme is truly unique and catalyses a reaction in a two-step mechanism”, comments Dr. Sissy Kalayil, who is one of the lead Frankfurt scientists on the project. “Our results are very exciting as they reveal atomic details of this mechanism, and make the rationale design of inhibitors possible.”

In their publication, the researchers also reveal how this bacterial effector probably chooses its victim proteins within the host cell, exerting its effect by attaching ubiquitin to them. They also developed a first inhibitor blocking this reaction in vitro. “Our basic discovery has allowed us to prove that these enzymes are druggable,” Dikic comments. “But it is early days. There is a long road ahead of us before we will be able to use this novel mechanism therapeutically. And we will surely not stop here.” Most likely, Legionella is not the only bacterium using this mechanism.

Ivan Dikic’s group is located at the Institute of Biochemistry II (Medical Faculty) and the Buchmann Institute for Molecular Life Sciences at Goethe University Frankfurt. The group investigates the role of ubiquitin in human diseases including cancer, amyotrophic lateral sclerosis and infectious diseases.

Publication: Kalayil S*, Bhogaraju S*, Bonn F, Shin D, Liu Y, Gan N, Basquin J, Grumati P, Luo Z-Q, Dikic I. Insights into catalysis and function of phosphoribosyl-linked serine ubiquitination. Nature, Advanced Online Publication, DOI 10.1038/s41586-018-0145-8.
* Shared first authorship

In the same issue of Nature, there will be two articles published by the groups of Yue Feng (China) and Yuxin Mao (USA) which contribute additional details to the molecular mechanism of this unique enzyme (DOI 10.1038/s41586-018-0146-7 und 10.1038/s41586-018-0147-6

Link to images: www.uni-frankfurt.de/72116155

Caption: A detailed view of the 3D structure of the enzymatic active part of SdeA toxin (green). On the left, the essential catalytic surface is depicted in orange and the area for binding target proteins in purple. On the right, the amino acid residues involved in the reaction are highlighted. The detailed molecular picture now enables the design of suitable inhibitors. Source: Nature/Kalayil et al, Mai 2018

Information: Dr. Kerstin Koch, Institute of Biochemistry II, University Hospital Frankfurt, Phone: +49 69 6301 84250, k.koch@em.uni-frankfurt.de

Goethe University is a research-oriented university in the European financial centre Frankfurt The university was founded in 1914 through private funding, primarily from Jewish sponsors, and has since produced pioneering achievements in the areas of social sciences, sociology and economics, medicine, quantum physics, brain research, and labour law. It gained a unique level of autonomy on 1 January 2008 by returning to its historic roots as a "foundation university". Today, it is among the top ten in external funding and among the top three largest universities in Germany, with three clusters of excellence in medicine, life sciences and the humanities. Together with the Technical University of Darmstadt and the University of Mainz, it acts as a partner of the inter-state strategic Rhine-Main University Alliance.

Current news about science, teaching, and society in GOETHE-UNI online (www.aktuelles.uni-frankfurt.de)

Publisher: The President of Goethe University
Editor: Dr. Anne Hardy, Press Information Officer, Phone: +49(0)69 798-12498, Fax +49(0)69 798-761 12531, hardy@pvw.uni-frankfurt.de, Internet: www.uni-frankfurt.de 

Jennifer Hohensteiner | idw - Informationsdienst Wissenschaft

Further reports about: Biochemistry Legionella Molecular antibiotics bacteria bacterial infection enzyme

More articles from Life Sciences:

nachricht Tiny Helpers that Clean Cells
14.08.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht Light-controlled molecules: Scientists develop new recycling strategy
14.08.2018 | Humboldt-Universität zu Berlin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

Im Focus: Lining up surprising behaviors of superconductor with one of the world's strongest magnets

Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur

What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...

Im Focus: World record: Fastest 3-D tomographic images at BESSY II

The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.

Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...

Im Focus: A molecular switch may serve as new target point for cancer and diabetes therapies

If certain signaling cascades are misregulated, diseases like cancer, obesity and diabetes may occur. A mechanism recently discovered by scientists at the Leibniz- Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin and at the University of Geneva has a crucial influence on such signaling cascades and may be an important key for the future development of therapies against these diseases. The results of the study have just been published in the prestigious scientific journal 'Molecular Cell'.

Cell growth and cell differentiation as well as the release and efficacy of hormones such as insulin depend on the presence of lipids. Lipids are small...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

2018 Work Research Conference

25.07.2018 | Event News

 
Latest News

Can radar replace stethoscopes?

14.08.2018 | Medical Engineering

The end-Cretaceous extinction unleashed modern shark diversity

14.08.2018 | Life Sciences

Light-controlled molecules: Scientists develop new recycling strategy

14.08.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>