We recently came across an interesting article on bacterial persisters and their awakening mechanism inMolecular cell.We were intrigued to learn more about this research field from Dorien Wilmaerts, the lead author of the paper.
Dorien explains that’s nowadays, healthcare systems face major challenges as antibiotic treatment options for bacterial infections are steadily running out. In addition to antibiotic resistance, a lesser-known mechanism called persistence, enables bacteria to survive treatment. In every bacterial population, a small number of cells temporarily display an antibiotic-tolerant phenotype that is attributed to an altered physiological state. These persisters do not grow, but they can recolonize the environment upon persister state exit.
In most cases, the immune system is capable of efficiently eradicating persisters. However, when disabled, persisters can survive and cause chronic infections, e.g. when pathogens reside in host cells, or in body sites that are difficult to reach, and in patients undergoing immuno-suppressive therapy. Despite their clinical importance, there are currently no available anti-persister therapies. Ideally, these therapies would rely on re-sensitizing persisters to the applied antibiotic by triggering exit from the persister state. However, to date, only limited studies have addressed how persisters awake and revert to the non-persister state.
Previous research from Dorien’s group has shown that the peptide HokB induces persistence by the formation of pores, resulting in membrane depolarization and ATP leakage. In theMolecular cellpaper, Dorien and her colleagues delineate the mechanisms responsible for the awakening of HokB-induced persister cells.
You have been working on the delineation of the persister bacterial cell awakening over the last few years. What excites you the most about your work?
When I started my PhD, I identified a few mutants in which HokB overexpression did not cause a high-persister phenotype. We could not make much sense of this data at the time and we slowly forgot about it. After we unraveled the pathway underlying HokB induced persistence, we were able to track down that these mutants had a defective awakening. I would never have thought that I could ever make sense of this ‘strange’ data and see them published.
What are the most essential skills required for a successful career in this research area?
I think an analytical mindset, perseverance and the ability to think outside the box are important skills for any young scientist.
From your perspective, what are the major challenges remaining in the study of bacterial persisters?
The field is struggling and suffering from controversies at the moment. Some paper retractions have cast a negative impression on persister research, which is a pity.
From a research perspective, I think a major challenge lying ahead is to find direct evidence of the clinical importance of persister cells in humans. Although there is a vast amount of circumstantial evidence, direct proof in humans is still lacking.
Bacterial persistence, as opposed to antibiotic resistance, is a relatively new notion among microbiologists. What does the future hold for this study area and what should we expect to learn within the next decade?
I think the field will be able to tackle the major challenges regarding the clinical importance of persister cells in humans and mechanisms of persister awakening. I expect that the continuous progress in single-cell techniques will facilitate the research on persister cells.
“In every bacterial population, a small number of cells temporarily display an antibiotic-tolerant phenotype that is attributed to an altered physiological state.
These persisters do not grow, but they can recolonize the environment upon persister state exit.”
You have been conducting amazing bench work so far. Have you ever thought of developing an in vivo model to study bacterial persistence in a more clinically relevant setting? Is it feasible, and what are the challenges?
Although it would be great to have anin vivomodel on bacterial persistence, this was not the focus of my research. I think it would indeed be feasible and there are already some papers describing persisters in anin vivocontext. Unfortunately,the small number of persister cells and the fact that their phenotype is only temporary complicates the practicality of such a model.
You have uncovered an important mechanism of bacterial persister cell awakening. Do you aspire to develop compounds that would“wake-up” the persister cells in order to use them as adjuncts to classic antibiotics? What are the challenges of developing such agents?
Using the delineated mechanism of the paper, we are indeed planning to start working on a screening platform, which eventually could be used to detect compounds that trigger persister awakening. However, the main challenge is the generality of this compound. It is unsure if such agents would be able to wake up all persisters, as the persister population is heterogeneous and, hence, the awakening mechanisms will be variable as well.
“Ideally, these therapies would rely on re-sensitizing persisters to the applied antibiotic by triggering exit from the persister state.
However, to date, only limited studies have addressed how persisters awake and revert to the non-persister state.”
Is there a scientist in the field that you lookup to and why do you admire him/her?
There are some great scientists working in the persister field. I like it when scientists dare to take risks and publish unexpected results. For example, the group of Prof. Helaine was the first one to show persistersin vivo,after which they were able to delineate interesting features ofSalmonellapersisters in macrophages. Moreover, Prof. Brynildsen has published important work, where the idea of persister cells as dormant cells was questioned. A view which is now shared by more and more labs.
Besides personal traits that led you to success in your study area, how have your mentors influenced your career so far? In your opinion, what are the specific characteristics of a mentor that help mentees grow both personally and professionally?
In our group, we have monthly personal meetings, which is a nice way to discuss obtained data from that month. In addition to regular guidance, I think that it is important for a mentor to be able to adapt to the needs of the PhD student and to know his or her strengths and weaknesses.
What would you say to someone who considers getting involved in bacterial persistence research?
Do it! There are so many more exciting discoveries awaiting. The field is also rather small, so you learn to know a lot of people during conferences.
Have you ever thought of transitioning to industry, or do you envision a career in academia and why?
I will defend my PhD in November, and afterwards I will start working as a postdoc in the lab of Prof. Jan Michiels. I have funding only for one year, so I am currently looking around. Ideally, I would prefer a career in academic research,so let’s see what the future brings.
Do you think there is place for the development of persistent-awakening or persister-prohibiting drugs in the industry now, or is it too early for companies to invest in such discoveries?
Research on persister awakening mechanisms is still in its infancy, so it might still be too early. Another factor that may be impeding interest from the pharma industry is the lack of direct evidence of a role for persisters in chronic infections in humans. However, I believe that in a couple of years these hurdles could be overcome, making persisters a more interesting investment case for pharmaceutical companies.