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Bioorg Med Chem. 2012 Jan 15;20(2):583-91. doi: 10.1016/j.bmc.2011.07.047. Epub 2011 Jul 29.

Development and characterization of improved β-lactone-based anti-virulence drugs targeting ClpP.

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Department Chemie, Center for Integrated Protein Science CIPSM, Technische Universität München, Institute of Advanced Studies IAS, Lichtenbergstrasse 4, 85747 Garching, Germany.


Here, we report the synthesis and in depth characterization of a second generation β-lactone derived virulence inhibitors. Based on initial results that emphasized the intriguing possibility to disarm bacteria in their virulence the present study develops this concept further and analyses the potential of this strategy for drug development. We were able to expand the collection of bioactive compounds via an efficient synthetic route. Testing of all compounds revealed several hits with anti-virulence activity. Moreover, we demonstrated that these molecules act solely by reducing virulence but not killing bacteria which is an important prerequisite for preserving the useful microbiome. Finally, incubation of lactones with eukaryotic cell lines indicated a tolerable cytotoxicity which is essential for entering animal studies.

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