21.03.2023

A protein as the key to antibiotic-resistant bacteria

Researchers from Tübingen find a protein that promotes resistance to Pseudomonas bacteria against antibiotics. Understanding the exact function of the protein YgfB might open doors to the identification of novel drug targets to fight infections caused by multiresistant Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a bacterium that occurs everywhere in the environment and can adapt well to it. For healthy people, contact with P. aeruginosa is usually harmless. For immunocompromised patients, however, this bacterium can become a danger. The consequences are severe infections, e.g. of the respiratory tract, which are difficult to treat even with antibiotics.

Researchers at the University of Tübingen and the Cluster of Excellence CMFI have now systematically investigated the connection between bacterial proteins and the defense mechanism against antibiotics, with the aim of developing new therapeutic approaches. The results of the study have now been published in the journal Communications Biology of the Nature Group.

The bacterium P. aeruginosa has a strategy against antibiotics

In the therapy of bacterial infections with P. aeruginosa, antibiotics that damage the cell wall or bacterial DNA, such as Ceftazidime or Ciprofloxacin, are usually used. However, P. aeruginosa is naturally resistant to a variety of antibiotics. In addition, an increase in multi-resistant Pseudomonas strains has been observed, making antibiotic therapies less and less successful.

An important defense mechanism of P. aeruginosa against antibiotics is the production of the enzyme β-lactamase. This enzyme destroys structures of β-lactam antibiotics, such as Ceftazidime, rendering them ineffective. The bacterium perceives when its cell wall is attacked and destroyed by antibiotics. If destruction of the cell wall occurs, degradation products (anhyd-MurNAc peptides) are formed that lead to an increased production of β-lactamases. These β-lactamases degrade antibiotics. The antibiotics become ineffective, the pathogen survives, and the infection can spread further.

A protein determines the success of therapy

The research team led by Erwin Bohn, research group leader at the Institute of Medical Microbiology and Hygiene at Tübingen University Hospital, now looked for bacterial proteins that influence the production of β-lactamases in multidrug-resistant Pseudomonas bacteria. The team discovered the protein YgfB, the function of which was previously unknown. Using molecular biology methods, the researchers succeeded in clarifying how YgfB indirectly stimulates the production of β-lactamases.

Namely, the protein YgfB interacts with the transcription factor AlpA and by doing this inhibits AlpA mediated production of the enzyme AmpDh3. This is a crucial step, because the AmpDh3 enzyme would otherwise destroy the peptides arising from the attacked bacterial cell wall (anhyd-MurNAc). Consequently, the higher abundance of these peptides now triggers increased production of β-lactamases. The β-lactamases are the critical factor at the end of this cascade that makes the bacteria less sensitive to antibiotics such as Ceftazidime. Thus, the protein YgfB indirectly leads to antibiotic resistance in bacteria.

“Understanding the plasticity of resistance mechanisms is important to adapt to the growing challenge of multi drug resistance and the first step in developing new therapeutic options,” says Erwin Bohn. The next step will be to develop strategies to interfere with the pathways involving YgfB action or to provoke high AmpDh3 production to break β-lactam resistance.

Leon Kokkoliadis/CMFI Cluster of Excellence