Compound Profiling und Screening
The skin and mucosa of all humans are colonized by a large number of different microorganisms. Among them are opportunistic pathogens, which switch from harmless commensal organisms into life-threatening pathogens in particular when the immune system is compromised, e.g. as consequence of a severe disease or of therapeutic interventions, such as chemotherapies or antibiotic treatment. Thus, these infections frequently develop on top of another severe disease causing complications and extended stays in critical care units of hospitals. To avoid the outbreak of those infections, antibiotics are prophylactically applied, which supports the emergence of antibiotic resistance. Hence, new therapeutic approaches are urgently needed.
New strategies for therapies of infections by commensal and persistent microorganisms
Both commensal and persistent microorganisms survive in the human host without causing any disease even for years. They are usually limited to defined, restricted niches of the human body. Under predisposing conditions of the host these microorganisms increasingly proliferate and spread out in the body causing severe infections. Thus, successful pathogens are able to flexibly adapt to different environmental conditions characterized for example by varying availabilities of nutrients, essential elements and oxygen or components of the immune system of the host.
We aim at the identification of new therapeutic agents addressing new molecular targets, which are relevant for the adaptation to the conditions in the infected host. Thus, we simulate the infectious situation already in our screening assays and study in detail the interactions between the microorganisms and host cells at a molecular level. The experimental work is supported by the establishment of mathematical models, which simulate the effect of chemical inhibitors in silico.
We have chosen the yeast Candida albicans as representative of a commensal organism and Mycobacteria as representatives of persistent bacteria.
The yeast Candida albicans colonizes the skin and mucosa of almost 70 % of the humans as part of the natural microbial flora without any symptoms of an infection. However, under predisposing conditions of the host the commensal yeast can switch into a pathogen. Infections range from localized superficial infections of the skin or oral or vaginal mucosa to life-threatening systemic mycoses.
As these infections are a serious problem in intensive care units of hospitals, antimycotics are often given prophylactically to prevent the outbreak of an infection. However, several existing antimycotics cause severe side-effects and the treatment regime causes the increase of resistant strains. Thus, we work on the development of new therapeutic strategies and new diagnostic tools for the identification of patients at risk.
Mycobacterium tuberculosis (Mtb) is the world's leading cause of death from a single infectious agent. Tuberculosis (TB) is epidemic with currently approximately 1.8 billion infected people. The complete eradication of Mtb from an infected patient is difficult largely due to the slow growth rates of this organism and its remarkable ability to persist in a so-called dormant state. This requires antibiotic treatment for several months, which is frequently not strictly followed resulting in incomplete sterilization and recurrent disease. The inevitable consequence of inadequate therapy is the emergence of highly resistant strains, which cannot be treated with the front-line antibiotics for Mtb. Thus, we have focussed on the search for new therapeutic agents, which allow to shorten therapy and which are also active against slow-growing or even dormant microorganisms. For safety reasons we use in our lab mycobacterium bovis (BCG) and mycobacterium smegmatis as test organisms.