title: The biofilm inhibitor Carolacton inhibits planktonic growth of virulent pneumococci via a conserved target.
abstract: New antibacterial compounds, preferentially exploiting novel cellular targets, are urgently needed to fight the increasing resistance of pathogens against conventional antibiotics. Here we demonstrate that Carolacton, a myxobacterial secondary metabolite previously shown to damage Streptococcus mutans biofilms, inhibits planktonic growth of Streptococcus pneumoniae TIGR4 and multidrug-resistant clinical isolates of serotype 19A at nanomolar concentrations. A Carolacton diastereomer is inactive in both streptococci, indicating a highly specific interaction with a conserved cellular target. S. mutans requires the eukaryotic-like serine/threonine protein kinase PknB and the cysteine metabolism regulator CysR for susceptibility to Carolacton, whereas their homologues are not needed in S. pneumoniae, suggesting a specific function for S. mutans biofilms only. A bactericidal effect of Carolacton was observed for S. pneumoniae TIGR4, with a reduction of cell numbers by 3 log units. The clinical pneumonia isolate Sp49 showed immediate growth arrest and cell lysis, suggesting a bacteriolytic effect of Carolacton. Carolacton treatment caused a reduction in membrane potential, but not membrane integrity, and transcriptome analysis revealed compensatory reactions of the cell. Our data show that Carolacton might have potential for treating pneumococcal infections.
authors.affiliation: Department of Medical Microbiology, Group Microbial Communication, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Jannik
authors.initials: J
authors.lastname: Donner
authors.affiliation: Department of Medical Microbiology, Group Microbial Communication, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Reck
authors.affiliation: Institute of Microbiology, Technische Universität Braunschweig, Braunschweig, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Bergmann
authors.affiliation: Institute of Organic Chemistry and Center of Biomolecular Drug Research (BMWZ), Leibniz Universität Hannover, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kirschning
authors.affiliation: Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Department of Medical Microbiology, Group Microbial Communication, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Wagner-Döbler
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects*; D018942:Macrolides / Q000494:pharmacology*; D009231:Myxococcales / Q000187:drug effects / Q000378:metabolism; D010933:Plankton / Q000187:drug effects*; D011008:Pneumococcal Infections / Q000188:drug therapy; D013295:Streptococcus mutans / Q000187:drug effects* / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D018942:Macrolides; C553423:carolacton