Why do some bacteria become resistant to penicillin, and what can we do about it? A new PhD thesis from the Norwegian University of Life Sciences (NMBU), provides fresh insight into the mechanisms behind resistance in one of the most common causes of pneumonia.
The doctoral research of Ragnhild Sødal Gjennestad sheds light on why certain pneumococcal bacteria become resistant to penicillin, and why it is so difficult to find a simple explanation.
Below, she answers three questions about her research:
Why is this research important?
Penicillin is widely used to treat respiratory tract infections. When such infections are caused by resistant bacteria, treatment is no longer effective. To develop new treatment strategies, it is crucial to understand the factors that contribute to bacterial resistance to penicillin.
What were the goals of you phd-work?
Several factors determine whether the pneumonia-causing bacterium Streptococcus pneumoniae is resistant to penicillin. Penicillin kills bacteria by inhibiting synthesis of the bacterial cell wall, which leads to cell lysis. Pneumococci protect itself from penicillin by changing the proteins that penicillin binds to. Then it can still produce a cell wall, and the bacteria survives the penicillin treatment. However, additional factors are also contributing to resistance. This PhD project aims to better understand some of these factors.
What are your most important results?
One of the factors I have investigated is the protein MurM. Our findings show that the role of this protein in penicillin resistance is more complex than previously thought. MurM influence the outer structure, the cell wall, of pneumococci and is important for penicillin resistance. It has long been believed that bacteria become resistant to penicillin by producing a more active version of this protein, leading to greater changes in the cell wall. However, our results do not support this assumption. We also demonstrate that earlier theories for why the MurM protein is important for resistance are not supported by our findings. Although the full role of MurM remains unresolved, our work helps narrow down where future research should focus.
Another factor I have studied is a small signalling molecule called cyclic di-AMP. This molecule regulates various processes within bacterial cells and affects penicillin resistance in many bacterial species, including Streptococcus pneumoniae. Exactly how cyclic di-AMP influences penicillin resistance is still not fully understood, although several hypotheses have been proposed. We show that this molecule regulates the bacteria’s ability to divide and form new cells. Although more research is needed to understand this regulation process, our results can help explain how cyclic di-AMP influences penicillin resistance.
In this work, I have also investigated potential adjuvant targets that could restore the effectiveness of penicillin against resistant pneumococci. By targeting processes important for penicillin resistance, it may be possible to make resistant bacteria susceptible again. We confirm previous findings that the MurM protein is a promising adjuvant target, but we did not identify any new targets that are effective across a broad range of pneumococcal strains.
While investigating these potential targets, we observed large differences between different pneumococcal strains. Factors that are important for penicillin resistance in one strain may not be important in another. Further research is needed to understand what drives these differences, but our results suggest that the mechanisms of penicillin resistance are more complex than previously assumed. Our findings also highlight the importance of using bacterial strains isolated from different patients when studying antibiotic resistance.
FAct box:
Ragnhild Sødal Gjennestad
- Bachelor’s degree in Biomedical Laboratory Science (NTNU, Trondheim) and Master’s degree in Cell and Molecular Biology (NTNU, Trondheim)
- From Stokke, Norway
- Completed her PhD at the Faculty of Chemistry, Biotechnology and Food Science, NMBU
- Main supervisor: Associate Professor Daniel Straume (NMBU)
- Co-supervisors: Professor Morten Kjos (NMBU), Dr. Vegard Eldholm (Norwegian Institute of Public Health)
- Title of the thesis: New insights into penicillin non-susceptibility in Streptococcus pneumoniae