title: Development and characterization of improved β-lactone-based anti-virulence drugs targeting ClpP.
abstract: 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.
authors.affiliation: Department Chemie, Center for Integrated Protein Science CIPSM, Technische Universität München, Institute of Advanced Studies IAS, Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Zeiler
authors.forename: Vadim S
authors.initials: VS
authors.lastname: Korotkov
authors.forename: Katrin
authors.initials: K
authors.lastname: Lorenz-Baath
authors.forename: Thomas
authors.initials: T
authors.lastname: Böttcher
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D049071:Endopeptidase Clp / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012756:Sheep; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D007783:Lactones; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D049071:Endopeptidase Clp