Legionella toxin: support conventional antibiotic therapy
Multi-resistant germs pose a growing threat to healthcare. The massive and often unnecessary use of antibiotics means that more and more pathogens are insensitive to medication. Researchers have now developed a new strategy to fight bacteria. This concept could complement conventional antibiotic therapy.
The increase in resistance to antibiotics presents the healthcare system with an ever increasing challenge. If such medications stop working, even small inflammations can become a big 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.
Carefree use of antibiotics
The increasing spread of resistance makes it increasingly difficult to treat common diseases such as pneumonia or salmonellosis effectively.
One of the causes of resistance is carefree use of antibiotics. According to a study, many doctors in Germany often prescribe such drugs only on suspicion.
In addition, antibiotics are also used against diseases against which they are completely ineffective.
The innovation gap in the development of new 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 Goethe University Frankfurt am Main has now developed a new strategy to fight bacteria.
The new method is presented in the journal "Nature".
Control microbial infections
A promising approach to bring microbial infections under control is to limit the damage in the cells and tissues locally, according to a message from the Frankfurt University.
To do this, the toxins released by the bacteria must be carefully levered out. The research team of Prof. Ivan Dikic, director of the Institute for Biochemistry II at Goethe University Frankfurt, has been working in this field for ten years.
"We believe that we can supplement conventional antibiotic therapy by specifically switching off bacterial effector proteins with rationally developed active ingredients," explains Dikic.
“This is how we can help the patient to cope with the infection. The concept is still relatively new, but is attracting more and more attention from scientists. ”
Toxic effector promotes the spread of bacteria
The team of Ivan Dikic tries to find out how the new strategy could be implemented using Legionella as an example. These bacteria cause pneumonia and are particularly dangerous for immunocompromised patients.
The Dikic team has recently been involved in the discovery of a new enzymatic mechanism by which Legionella take control of their host cells.
“We have shown that Legionella using an enzyme, SdeA, cancels out one of the most important cellular mechanisms for protection against stress, namely the ubiquitin system. SdeA is therefore a toxic effector that promotes the spread of bacteria in the cell, ”explains Dr. Sagar Bhogaraju, who works in the Dikic laboratory at the Buchmann University Institute for Molecular Life Sciences.
Now Ivan Dikic's group has made another breakthrough: they were able to elucidate the atomic structure of SdeA and find out how the bacterial enzyme presumably selects its cellular “victims”.
SdeA works by attaching ubiquitin to the host cell proteins. The enzyme is unique in its mechanism by which it catalyzes a two-step reaction, comments Dr. Sissy Kalayil, one of the leading Frankfurt scientists in the project.
"Our results are extremely exciting because they clarify the process in atomic detail and thus enable the rational design of inhibitors."
The researchers have already developed a first inhibitor that can at least block the Legionella enzyme in the test tube.
“By elucidating the basic structure, we have now been able to prove that these bacterial enzymes can be attacked in a targeted manner. However, there is still a long way to go before we can potentially use the new mechanism therapeutically, ”says Dikic.
"But we stay tuned, because Legionella are probably not the only bacteria that use this mechanism." (Ad)