title: Synthesis of new carolacton derivatives and their activity against biofilms of oral bacteria.
abstract: Carolacton, a secondary metabolite isolated from the extracts of Sorangium cellulosum, causes membrane damage and cell death in biofilms of the caries- and endocarditis-associated bacterium Streptococcus mutans. Here, we report the total synthesis of several derivatives of carolacton. All new structural modifications introduced abolished its biological activity, including subtle ones, such as inversion of configuration at C9. However, a bicyclic bislactone derivative as well as the methyl ester of carolacton resulted in compounds with prodrug properties. Their inhibitory activity on S. mutans was proven to be based on enzymatic hydrolysis by S. mutans which provided native carolacton resulting in biofilm damage in vivo. Moreover, we demonstrate that carolacton acts also on S. gordonii, S. oralis and the periodontitis pathogen Aggregatibacter actinomycetemcomitans, causing elongated cells and growth inhibition.
authors.affiliation: Department of Prosthetic Dentistry and Biomedical Materials Science, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Stiesch.Meike@mh-hannover.de Stumpp.Nico@mh-hannover.de.
authors.forename: N
authors.initials: N
authors.lastname: Stumpp
authors.forename: P
authors.initials: P
authors.lastname: Premnath
authors.forename: T
authors.initials: T
authors.lastname: Schmidt
authors.forename: J
authors.initials: J
authors.lastname: Ammermann
authors.forename: G
authors.initials: G
authors.lastname: Dräger
authors.forename: M
authors.initials: M
authors.lastname: Reck
authors.forename: R
authors.initials: R
authors.lastname: Jansen
authors.forename: M
authors.initials: M
authors.lastname: Stiesch
authors.forename: I
authors.initials: I
authors.lastname: Wagner-Döbler
authors.forename: A
authors.initials: A
authors.lastname: Kirschning
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009055:Mouth / Q000382:microbiology*; D009231:Myxococcales / Q000378:metabolism; D013295:Streptococcus mutans / Q000187:drug effects / Q000254:growth & development*
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; C553423:carolacton