Synthesis of small molecules for inhition of chlamydial growth

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We have developed ceramide derivatives with potent anti-chlamydial activity. Potency, structure, in vitro assays and preliminary comparative studies between different chlamydial strains with known anti-chlamydial compounds suggest that these molecules have a novel not yet described mechanism of action. Our preliminary SAR, based on about 30 different compounds however indicates that most likely sphingolipid-specific biomolecules are targeted that could be important components of the chlamydial sphingolipid-acquisition machinery. Our objective is to further develop collections of molecules and to test their effect on the chlamydial life cycle. Chemical synthesis and various bioassays will be applied to identify potent effectors. We will synthesize variants of these effectors that will enable us to crosslink, pull down and identify potential molecular target molecules. Probes are envisioned allowing for dissecting molecular conversion and trafficking of individual lipids within infected cells. An additional important goal is to identify potential pharmaceutical targets and to establish in vitro assays that allow for rapid development of novel antichlamydial compounds. If host biomolecules are targeted by the compounds, it is well possible that these targets could also be interesting to be investigated with regard to other intracellular pathogens. The proposal covers chemical synthesis and bioorganic assay development on the one hand and cell- and infection biology on the other hand.