In 2018, the Foundation for prevention of antibiotics resistance awarded a total of four million SEK in research support to four researchers. During the spring we will present them and their projects in this newsletter.
Read about Peter Bergman’s, Karolinska Institutet, research on new therapeutic strategies for treating infections. These include substances such as vitamin D, which activate our immune system and then kill bacteria that cause diseases.
Peter Bergman, Associate professor, Clinical Microbiology,
Can you briefly describe your research project?
We study how the innate immune system kills bacteria. This part of the immune system is what takes care of microbes during the first minutes to hours of a bacterial infection. The effectors, i.e. the molecules with antibacterial action, are antimicrobial peptides (AMPs), reactive oxygen species (ROS) and autophagy, which directly kill the bacteria.
In our research, we have identified a number of drugs that can activate these innate effector systems at our mucosal surfaces and in immune cells. For example, vitamin D is such a drug that directly induces AMP-production in many cell types, including epithelial- and immune-cells. We have performed several clinical trials where vitamin D was shown to be partly beneficial in patients with pulmonary tuberculosis and with bacterial and viral respiratory tract infections.
Recently, we identified a new class of AMP-inducers that will now be evaluated in a cellular infection model against multidrug resistant bacteria. This model enables a rapid evaluation of many novel drug candidates alone and also together with conventional antibiotics. Preliminary data show promising results with one novel compound synthesized by us with significant activity against carbapenemase-producing Klebsiella pneumoniae and especially together with conventional antibiotics.
How will the funds from the Foundation contribute to your work?
First, I would like to say that I am grateful for receiving this grant. In addition, I am very happy to see that the Foundation has been brave to support research where the immune system can be used as a way to prevent or treat bacterial infections. This is an area with great potential but prior to this call, the funding to projects in this area has been limited.
I will use the money to continue with our cellular infection model and also to plan for follow-up experiments in a mouse model. Specifically, the money will partly support a postdoctoral fellow in my laboratory during the two years period that was granted.
In what way will your work help to decrease the development of antibiotic resistance?
Our results show that the AMP-inducing approach is effective against MDR Klebsiella-strains. Notably, the best effect is when we combine the AMP-inducer with cefotaxime. This antibiotic is normally not active against MDR Klebsiella-strains but together with the combined attack from the immune system it becomes susceptible again.
Thus, the need to use carbapenems or colistin, which are considered to be third line or last resort antibiotics, is greatly reduced. Combined, our approach to boost immunity could prolong the use of conventional antibiotics and save the more expensive and less available antibiotic classes for cases where they are really needed.
How is it that you ended up in the field of antibiotic resistance?
During my clinical work in the bacteriology laboratory at the Karolinska University Hospital, I became involved in clinical cases where bacteria were found to be resistant against almost all available antibiotic classes. At the same time I knew from my work in the research laboratory that many of these bacteria were susceptible to antimicrobial peptides and to other innate effectors, such as ROS and autophagy. This fueled a thought that the two systems – conventional antibiotics and AMPs/ROS/autophagy – could be combined as a novel treatment against MDR bacterial infections.
Since AMPs are difficult to give per se due to high costs and risk of degradation in blood, we have developed the concept of AMP-induction, i.e. we develop drugs that improve endogenous AMP-production at the site of infection.
Today, I share my time between the research laboratory and clinical work with patients with an impaired immune system.
When can you hopefully see any results from your project?
At present we are optimizing the cellular infection model and have obtained very promising results. As next step we will plan for proof-of-concept studies in mice and if these are successful we will seek for more funding for clinical trials.
However, it should be noted that the most active component that we have found constitutes a new chemical entity, which means that it will take considerable time, at least five years, before it can enter into a clinical trial in humans.
How does your research contribute to the public?
I think it is important to bring in the immune system into the discussion about antibiotic resistance. In fact, most of us do not suffer from MDR infections, which is comforting and the immune system is constantly patrolling our mucosal surfaces with great success. During exceptional situations we can be infected and sometimes the bacteria are resistant against many antibiotic drugs. This is unfortunate and connected with higher mortality and increased costs for the healthcare system. Therefore, there is a great need to continue with research into all aspects of this area, including antibiotic stewardship, surveillance but also searching for the next generation of antibiotic drugs.
The problem is that any new drug that directly kills the bacteria will exert a selection pressure on the bacterial community and resistant mutants will escape. This is the reason why immune mediated approaches also should be developed, since the chance for development of bacterial resistance against the plethora of immune mediated antibacterial mechanisms, is simply very low.
I strongly believe that we will not gain control of the MDR epidemic unless we also obtain full understanding and control of the immune system in relation to bacterial infections.