Department Chemie, Center for Integrated Protein Science CIPSM, Technische Universität München, Institute of Advanced Studies IAS, Lichtenbergstrasse 4, 85747 Garching, Germany.
Bioorg Med Chem. 2012 Jan 15;20(2):583-91. doi: 10.1016/j.bmc.2011.07.047. Epub 2011 Jul 29.
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.
在这里，我们报告了第二代β-内酰胺衍生的毒力抑制剂的合成和深入表征。基于最初强调以有趣的可能性削弱细菌毒力的结果，本研究进一步发展了这一概念，并分析了这一策略在药物开发方面的潜力。我们能够通过有效的合成路线扩展生物活性化合物的集合。对所有化合物的测试揭示了几种具有抗毒力活性的化合物。此外，我们证明这些分子仅通过降低毒力起作用，而不会杀死细菌，这对于保留有用的微生物组至关重要。最后，内酯与真核细胞系孵育表明具有可容忍的细胞毒性，这对于进入动物研究至关重要。
