title: The ClpP peptidase of Wolbachia endobacteria is a novel target for drug development against filarial infections.
abstract: BACKGROUND
  Filarial infections causing lymphatic filariasis or onchocerciasis (river blindness) can be treated with antibiotics (e.g. doxycycline) targeting the essential endosymbiotic Wolbachia bacteria. The depletion of Wolbachia inhibits worm development and causes worm death. Available antibiotics have restrictions for use in children and pregnant or breastfeeding women. Therefore, alternative antibiotics are needed that can be given to all members of the population and that are active with a shorter therapy time. Antibiotics of the acyldepsipeptide class have been shown to inhibit the growth of bacteria by overactivating the peptidase ClpP. The novel mode of action of this class of antibiotics could lead to faster killing of intracellular bacteria.
  
  
  OBJECTIVE
  To characterize acyldepsipeptide activity against the Wolbachia ClpP.
  
  
  METHODS
  The activity of acyldepsipeptides was investigated against Wolbachia in vitro in insect cells and also against worms in culture. In addition, structural effects were investigated by fluorescence microscopy and electron microscopy. The activity of ClpP was also investigated in vitro.
  
  
  RESULTS
  We show that acyldepsipeptides are active against recombinant Wolbachia ClpP and endobacteria resident within insect cells in vitro, and some derivatives were also active against filarial worms in culture. As a consequence of treatment, the worms became immotile and died, the latter confirmed by a viability assay.
  
  
  CONCLUSIONS
  The mode of action of the acyldepsipeptides in Wolbachia is the dysregulation of ClpP, causing the uncontrolled degradation of proteins, including the cell division protein FtsZ. Our results demonstrate that wolbachial ClpP is a target for further antifilarial antibiotic discovery.
authors.affiliation: Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schiefer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vollmer
authors.forename: Christine
authors.initials: C
authors.lastname: Lämmer
authors.forename: Sabine
authors.initials: S
authors.lastname: Specht
authors.forename: Christian
authors.initials: C
authors.lastname: Lentz
authors.forename: Helga
authors.initials: H
authors.lastname: Ruebsamen-Schaeff
authors.forename: Heike
authors.initials: H
authors.lastname: Brötz-Oesterhelt
authors.forename: Achim
authors.initials: A
authors.lastname: Hoerauf
authors.forename: Kenneth
authors.initials: K
authors.lastname: Pfarr
mesh_terms: D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology*; D047630:Depsipeptides / Q000302:isolation & purification / Q000494:pharmacology*; D049071:Endopeptidase Clp / Q000037:antagonists & inhibitors*; D005369:Filaricides / Q000302:isolation & purification / Q000494:pharmacology*; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D011480:Protease Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D020577:Wolbachia / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000648:ultrastructure
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D005369:Filaricides; D011480:Protease Inhibitors; D049071:Endopeptidase Clp
keywords: FtsZ; Litomosoides sigmodontis; acyldepsipeptides; filariasis