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

• Published in: Bioorganic & medicinal chemistry 2012-01, Vol.20 (2), p.583-591
• Main Authors: Zeiler, Evelyn, Korotkov, Vadim S., Lorenz-Baath, Katrin, Böttcher, Thomas, Sieber, Stephan A.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; bacteria; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Beta-lactones; chemistry; cytotoxicity; Disarming pathogens; drugs; Endopeptidase Clp - antagonists & inhibitors; Endopeptidase Clp - genetics; Endopeptidase Clp - metabolism; Erythrocytes - drug effects; eukaryotic cells; lactones; Lactones - chemical synthesis; Lactones - chemistry; Lactones - pharmacology; microbiome; MRSA; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sheep; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Virulence
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.07.047

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.