Analysis of the mechanisms of action of anti-infectives

Anti-infectives ideally affect such structures in the cells of the pathogens that are not present in human cells. Most agents, which are used as antimycotics in clinics, target specific fungal cell wall or cell membrane components, because human cells do not have cell walls and fungal cell membranes contain ergosterol, which is not present in human cells. In addition microbial two-component signal transduction systems are discussed as possible drug targets. These systems comprise sensor and regulator domains or proteins, with which microorganisms detect changes in their environment, such as the lack of nutrients and cell wall damage or osmotic stress, and regulate the adaptation to these changes. Thus, these systems are essential for the survival of the microorganisms under changing environmental conditions, but are not present in human cells. Histidine kinases are central elements of two-component systems. They were originally found in bacteria, but are also present in fungi. Agricultural phenylpyrrole and dicarboximide fungicides specifically target type III histidine kinases in fungal plant pathogens. Thus, we tested the activity of those compounds on human fungal pathogens. Candida albicans has three histidine kinases, among which is CaNik1, a type three histidine kinase. We could show that this protein is the target of the mentioned agricultural fungicides, but also of the myxobacterial secondary metabolite ambruticin. Treatment of C. albicans with these compounds activates a mitogen activated protein kinase (MAPK) cascade, which is involved in the regulation of numerous stress responses. We now investigate the function of the histidine kinases and of the interaction between the protein and the chemicals in more detail to explore the potential of this pathway as drug target.


Funding Agency

HZI - Helmholtz Centre for Infection Research