| Within the four main classes of cell components, e.g. nucleic acids, proteins, carbohydrates and lipids, the latter two stand out as being extremely heterogeneous. In addition, the molecular structure of carbohydrates and lipids does not follow directly from the genome and isolation of individual components is often prohibitively difficult. Their availability is nevertheless a conditio sine qua non for understanding cellular processes and this leads to a key role for Organic Chemistry in the study of the function of carbohydrates and lipids and their application in Medicine. I want to establish a research line in Chemical Biology with a focus on the emerging field of Lipidomics. This VICI-proposal focuses on mycobacteria, the cause of world-wide infectious diseases such as tuberculosis. The complex cell wall lipids of mycobacteria are responsible for pathogenicity. I plan to prepare all important classes of mycobacterial cell wall lipids by chemical synthesis. The synthetic approach is based on new catalytic reactions that are developed in my department. This combination of catalysis and synthesis is unique in The Netherlands and brings for the first time these very complex lipids within reach. The role of individual (glyco)lipids in virulence, immune response and impermeability of the bacterial cell wall will be studied using Chemical Biology. This approach builds on my recent stay as a guest professor in the Chemical Biology department at the Max Planck Institute for Molecular Physiology. Together with Prof. Bertozzi (Berkeley), Prof. Moody (Harvard), and Dr. Van Soolingen (RIVM) I aim at significant progress towards improved vaccines and drugs against mycobacterial diseases. Project 1: Blocking Ag85; allowing antibiotics to enter M. tuberculosis Project 2: Combinatorial synthesis of mycobacterial lipids using a light-fluorous synthesis strategy Project 3: Uncovering the secret of Freund?s Adjuvant Project 4: On the hypervirulence of the Beijing strain of M. tuberculosis |
