title: Disorazoles Block Group A Streptococcal Invasion into Epithelial Cells Via Interference with the Host Factor Ezrin.
abstract: Bacterial pathogens use invasion into human cells as a strategy to escape not only the host's immune response, but also anti-bacterial treatment. This often leads to persistence and enables reinitiation of the infection process at a later time point. Here, we show that a family of myxobacterial metabolites, disorazoles, block invasion of group A Streptococcus (GAS) into human epithelial cells. Mechanistically, disorazoles target ezrin, a host protein involved in linking microfilaments to the membrane, and affect invasion most likely by interfering with dynamic phosphorylation of ezrin. Overall, our study suggests ezrin as a new factor in two different GAS invasion pathways, independent of the already known CD44 pathway, and that disorazoles are promising "pathoblocker" compounds aimed at this additional invasion mechanism.
authors.affiliation: Department of Microbial Natural Products (MINS), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI) and Institute for Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrücken, Germany; Central Facility for Microscopy (ZEIM), Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany; Department of Medical Microbiology (MMIK), Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany; German Centre for Infection Research (DZIF), Partner Site Braunschweig-Hannover, Hannover, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rox
authors.affiliation: Central Facility for Microscopy (ZEIM), Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.affiliation: Department of Medical Microbiology (MMIK), Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
authors.forename: Gursharan Singh
authors.initials: GS
authors.lastname: Chhatwal
authors.affiliation: Department of Microbial Natural Products (MINS), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI) and Institute for Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrücken, Germany; German Centre for Infection Research (DZIF), Partner Site Braunschweig-Hannover, Hannover, Germany. Electronic address: rolf.mueller@helmholtz-hzi.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099149:Ezrin
chemical_list: D000900:Anti-Bacterial Agents; D003598:Cytoskeletal Proteins; D010080:Oxazoles; D000099149:Ezrin; C092171:disorazol A
keywords: Group A Streptococcus; SfbI; Streptococcus pyogenes; adherence; disorazole; ezrin; invasion; myxobacteria