New active ingredient against chronic infections discovered

Can chronic infections be treated with a new active ingredient in the future?
Chronic infections are often difficult to treat and are associated with considerable health problems for those affected. A new active ingredient could significantly improve therapy options in the future, according to the results of a recent study by the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the German Center for Infection Research (DZIF).

"Chronic lung infections caused by the bacterium Pseudomonas aeruginosa require," according to the researchers, "complex and mostly permanent therapy with antibiotics." However, complete cure or at least increased suppression of the bacterial load is generally not possible. However, hope is offered by an optimized anti-infective agent with a new mechanism of action, which the scientists tested in their current study.

Block pathogenicity of the bacteria
New drugs against chronic lung infections are urgently needed and the researchers say they have now achieved an important breakthrough. You have successfully adapted an anti-infective agent with a new mechanism of action for the treatment of chronic lung infections. The starting point was a substance that can block the pathogenicity of the bacterium and weaken its biofilm protective shield, the scientists report. Altogether, the Helmholtz Validation Fund, the DZIF and the Helmholtz Center for Infection Research have invested a total of 2.7 million euros in the optimization of this substance class - "with the aim of a preclinical development candidate."

Bacteria are not killed
Dr. Martin Empting, who carried out the project at HIPS / HZI together with Prof. Rolf Hartmann and Dr. Thomas Hesterkamp, ​​emphasizes that the researchers have high hopes for these drug candidates. The so-called pathoblocker acts differently from an antibiotic and does not kill the bacterium, but rather interferes with its ability to damage the host and to protect itself from the immune system through biofilm formation. This "makes the bacterium more susceptible to parallel antibiotic therapy," said Dr. Empting continues.

Pseudomonas aeruginosa is a dangerous hospital germ
According to the researchers, the active ingredient, which attacks the bacterial receptor PqsR (also called "MvfR"), has a selective and specifically directed action against Pseudomonas aeruginosa. This would spare other bacteria that could also be useful. According to the scientists, it is also feared as a hospital germ and is listed on the "Priority Pathogens List" of the World Health Organization (WHO) as one of the three most important pathogens for the development of new active substances. The bacterium affects the respiratory and urinary tract or wounds and triggers dangerous infections. Their treatment has been extremely difficult to this day.

Risk patients for chronic lung infection
According to the researchers, corresponding chronic infections are particularly often affected by “patients suffering from cystic fibrosis.” The pathogen causes a chronic lung infection in them, which must be kept in constant control with antibiotics. Furthermore, patients with obstructive respiratory diseases or enlarged bronchi (so-called bronchiectasis) are increasingly affected by infections with the pathogen. Increasing resistance to antibiotics also made successful treatment more difficult for them.

Virulence process suppressed and biofilm formation reduced
In their investigations, the scientists were able to demonstrate that the starting molecule offers good conditions for the development of a successful active ingredient. The pathoblocker inhibits the function of the PqsR receptor, which plays a key role in the infection process of Pseudomonas aeruginosa. "The bacterium uses this receptor to regulate its group-specific virulence and thus factors that are responsible for the severity of the infection," reports the DZIF. The virulence process is suppressed on the one hand by the new active ingredient and on the other hand it has been proven to lower “also the mass of biofilm, a matrix that is formed by pseudomonas and protects the bacteria from attacks by the immune system.” With the formation of a biofilm, an infection becomes in usually chronic and difficult to treat.

Further development into a practically applicable active ingredient is planned
In the next step, according to the researchers, the drug designers are asked to change the structure of the molecule so that it has the properties necessary for an drug. For example, high effectiveness at the target structure, high selectivity and good availability at the site of action must be guaranteed. The aim of the research is to determine a preclinical profiling candidate in the next two years, which can then be further developed in collaboration or as part of a company spin-off.

"At the end of the development, there should be an active ingredient that can be inhaled by patients with chronic lung infections," emphasizes Dr. Empting. A promising first area of ​​application is the use as an accompanying therapy for antibiotic treatment. The development of pathoblockers, according to Dr. However, empting is fundamentally "an important option to get a lasting grip on the problem of chronic infections that are difficult to treat." (Fp)

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