The Department of Molecular and Applied Microbiology is devoted to research in the two main areas of the Leibniz-Institute of Natural Product Research and Infection Biology (HKI).

During the past 20 years, the incidence of fungal infections in humans has risen considerably. This increase in infections is associated with excessive morbidity and mortality and is directly related to increasing patient populations at risk for the development of serious fungal infections, which includes individuals undergoing solid-organ transplantation, blood and marrow transplantation, major surgery, and those with AIDS, neoplastic disease, immunosuppressive therapy, advanced age, and premature birth. Fungal infections are categorised in two groups: topical and systemic infections. Topical fungal infections affect body surfaces and can be chronic. Systemic fungal infections can occur in an organ or in the whole body and are transferred via the bloodstream. Compared to other microbial infections, systemic fungal infections are characterised by lower frequencies but generally high mortality rates (30-100%). The most common causes of systemic infections are Candida spp., in particular C. albicans, and Aspergillus spp., mainly A. fumigatus.

Aspergillus fumigatus has become the most important airborne fungal pathogen of humans. Diseases caused by A. fumigatus can be divided into three categories: allergic reactions and colonisation with restricted invasiveness are observed in immunocompetent individuals while systemic infections with high mortality rates occur in immunocompromised patients. Specific diagnostics are still limited as are the possibilities of therapeutic intervention, leading to the disappointing fact that invasive aspergillosis is still associated with a high mortality rate that ranges from 30% to 90%. For example, during the past 15 years, invasive aspergillosis has become the main cause of death in patients with acute leukemia and liver transplantation. A recent retrospective study on the risk and outcome of Aspergillus infections from 251 lung transplant recipients led to the finding that Aspergillus was isolated from 86 (33%) cases, which involved colonisation (n=50), tracheobronchial lesions (n=17) or invasive aspergillosis (n=19). Also, a significant association was found between acute rejection and the time at which fungal infections was diagnosed. The mortality rate for invasive infections was 78%.
In recent years considerable progress has been made in understanding the genetics of A. fumigatus and molecular techniques for the manipulation of the fungus have been developed. Molecular genetics offers not only approaches for the detailed characterisation of gene products that appear to be key components of the infection process but also selection strategies that combine classical genetics and molecular biology to identify virulence determinants of A. fumigatus. Furthermore, the genome of A. fumigatus has been sequenced. This knowledge provides an excellent opportunity to analyse fungal infection mechanisms in a broad sense.
Research at the Department covers all relevant aspects of A. fumigatus to elucidate the pathobiology of A. fumigatus. Research includes the areas of physiology/biochemistry, signal transduction, improvement of genetic techniques, genomics, proteomics, transcriptomics, glycoconjugates, pathogen / host (immune effector cells) interaction and an animal model is available. The Brakhage group has identified the first virulence determinant of A. fumigatus which is represented by the pksP gene involved in the biosynthesis of the conidial pigment. Based on results obtained in the Department, the identified proteins involved in virulence will be evaluated as target proteins for antifungal drugs.

Fungi produce numerous of secondary metabolites. Some of these compounds are used as antibiotics such as the ß-lactam antibiotics penicillin and cephalosporin, or as immunosuppressants like cyclosporin. Others have been proposed to be important for virulence e.g. of the human-pathogenic fungus Aspergillus fumigatus. Besides the identification and characterisation of novel microorganisms producing secondary metabolites, recent research at the Department has aimed at elucidating the molecular regulation of the biosyntheses of secondary metabolites, i.e., to answer quesions as under which physiological conditions are gene clusters expressed, what kind of regulatory genes are involved. The knowledge of the expression level of biosynthesis genes is of great importance for the production of secondary metabolites. Moreover, the identification of regulatory genes and circuits will help to elucidate both the physiological meaning of these compounds for the producing fungus and the extra- and intracellular signals controlling the biosyntheses of secondary metabolites in fungi.

Because of the amount of data generated in the different projects, a Systems Biology approach has been integrated in the Department’s effort to fully understand both infectious processes and the physiology of secondary metabolites. Therefore, in vivo, in vitro and in silico approaches have been brought together to discover the structure and dynamics of biological systems by process data analysis and modelling, as well as to control or optimise experiments (model based experimental design), biotechnical product formation and medical processes in diagnostics and therapy.