Our research aims to design and identify substances that can inhibit bacterial virulence and dismantle their mechanism of action.
Microbial infections are one of the world's most acute threats to public health. In the fight against infections, antibiotics are used that have long been considered a miracle cure for treating such infections. Development of new antibacterial drugs has been virtually stagnant for the past 50 years. In the meantime, however, available antibiotics have lost ground due to the emergence of resistant “superbacteria”. This means that a previously harmless infection or a simple surgical procedure can now be fatal. The classic type of antibiotic either blocks growth or kills the bacterium. Although effective, the main disadvantage of these types of antibiotics is that they generate a large selective pressure for resistance to occur, ie that bacteria develop that can grow in the presence of the antibiotic. One way to avoid such a development of resistance is to develop drugs that can deactivate the bacterium's virulence ability, ie its ability to infect the host organism (animal or human). The idea here is that if the substances do not kill the bacterium, they also do not exert any strong selection pressure on the bacterium to develop resistance. Another advantage is that our normal intestinal flora is not affected by drugs targeting the virulence of pathogenic bacteria.
Virulence briefly describes the ability of a bacterium to cause disease in a host cell. To be able to do this, bacteria have developed systems so that they can find their target cells and avoid the host organism's defense system. Through these systems, bacteria can sense changes in their environment that tell when it is the right time for infection and growth. These changes can be, for example, differences in pH, temperature, salinity and concentration of other molecules. In addition, if the bacterium can form its own toxin, the virulence is further enhanced.
We work in a team of several research groups active at Umeå University, which together with national and international partners have unique expertise in the disciplines of microbiology, cell and molecular biology, chemistry and structural biology. Our goal is to design and identify substances that can inhibit bacterial virulence and dismantle their mechanism of action. Our long-term vision is to recognize new therapeutic treatments for bacterial infections by focusing on the inhibition of bacterial pathogenesis.
As a model system, we use Listeria monocytogenes (Lm), a gram-positive bacterium that can cause serious illness, mainly in people with weakened immune systems, the elderly and pregnant women. Our research is focused on a transcription factor in Lm, called PrfA, which acts as the main regulator of virulence gene expression and which plays a central role in the conversion of Lm from a harmless saprophyte to a human pathogenic bacterium. We have previously identified a specific class of molecules, so-called 2-pyridones consisting of two complex ring systems, which can attenuate the pathogenicity of Lm. The purpose of our project is to further develop these substances towards functional drugs. With the help of X-ray crystallography, we want to study how new modified substance analogues bind to PrfA, which will be able to enable us to develop and improve these further. The effect of the substances on PrfA is also evaluated both in vitro and in vivo with established biochemical and biological analysis methods.
Our group specializes in structure-function studies on how PrfA activity is regulated in its various environments - outside and inside the host cell - will contribute valuable knowledge for the design of inhibitory molecules. To understand the infection biology of the pathogenic microorganism, as well as the response from the infected host, we study how various factors in the cell environment, such as pH, redox and oxidative stress, temperature and the presence of natural peptides, control PrfA regulation. This way we aim to generate a new understanding of the molecular mechanisms underlying virulence activation in Lm.
PrfA belongs to a large family of transcription factors called Crp – Fnr within which many factors are involved in virulence. There are therefore great opportunities that our research on how the activity of PrfA is regulated in Lm leads to knowledge that can be applied to other pathogens.