Successfully combat bacterial infections with a new antibiotic alternative

Legionella toxin: support conventional antibiotic therapy

Multidrug-resistant bacteria are a growing threat to healthcare. The massive and often unnecessary use of antibiotics means that more and more pathogens are insensitive to drugs. Researchers have now developed a new strategy to fight bacteria. This concept could complement conventional antibiotic therapy.

Challenge for healthcare

The increase in antibiotic resistance is posing a growing challenge for healthcare. When such drugs stop working, even small infections can become a major risk. German researchers have now developed a new strategy to fight bacteria. The experts have elucidated the molecular mechanism of action of a Legionella toxin and developed a first inhibitor (inhibitor).

Antibiotic resistance poses a threat to global health. German researchers have now developed a new strategy to fight bacteria. (Image: nenetus / fotolia.com)

Carefree use of antibiotics

The increasing prevalence of resistance makes it increasingly difficult to effectively treat common diseases such as pneumonia or salmonellosis.

One of the causes of resistance is the carefree use of antibiotics. For example, many physicians in Germany often prescribe such medications only on suspicion, according to a study.

In addition, antibiotics are used against diseases for which they are completely ineffective.

The innovation gap in the development of novel active substances, which has existed for more than 30 years, also contributed to the problem of resistance.

A working group headed by Prof. Ivan Dikic from the Goethe University Frankfurt am Main has now developed a new strategy to combat bacteria.

The new method is presented in the journal "Nature".

Control microbial infections

A promising approach to control microbial infections is to localize the damage in cells and tissues, according to a statement from the Frankfurt University.

For this purpose, the toxins released by the bacteria must be targeted. The research team of Prof. Ivan Dikic, director of the Institute of Biochemistry II at Goethe University Frankfurt, has been working in this field for ten years.

"We believe we can complement conventional antibiotic therapy by targeting bacterial effector proteins with rationally-engineered drugs," explains Dikic.

"That way, we can help patients cope with the infection. The concept is still relatively new, but it is attracting more and more attention among scientists. "

Toxic effector promotes spread of bacteria

How the new strategy could be implemented, the team of Ivan Dikic tries to find out from the example of Legionella. These bacteria cause pneumonia and are particularly dangerous to immunocompromised patients.

More recently, the Dikic team has been involved in the discovery of a new enzymatic mechanism that allows legionella to take control of their host cells.

"We have shown that Legionella, with the help of an enzyme, SdeA, blocks one of the most important cellular mechanisms of stress protection, the ubiquitin system. SdeA is therefore a toxic effector that promotes the spread of bacteria in the cell. " Sagar Bhogaraju, who works at the University Buchmann Institute of Molecular Life Sciences in Dikic's lab.

The group of Ivan Dikic has now made another breakthrough: she has been able to elucidate the atomic structure of SdeA and to find out how the bacterial enzyme presumably selects its cellular "victims".

SdeA works by attaching ubiquitin to the proteins of the host cell. The enzyme is unique in its mechanism by which it catalyses a two-step reaction. Sissy Kalayil, one of the leading Frankfurt researchers in the project.

"Our results are extremely exciting because they elucidate the process in atomic detail, allowing the rational design of inhibitors."

Inhibitor developed

A first inhibitor that can block the Legionella enzyme at least in the test tube, the researchers have already developed.

"By elucidating the basic structure, we were now able to prove that these bacterial enzymes are specifically vulnerable. However, there is still a long way to go before we can possibly use the novel mechanism therapeutically, "says Dikic.

"But we stay tuned, because most likely, Legionella are not the only bacteria using this mechanism." (Ad)