title: A cell-based screen reveals that the albendazole metabolite, albendazole sulfone, targets Wolbachia.
abstract: Wolbachia endosymbionts carried by filarial nematodes give rise to the neglected diseases African river blindness and lymphatic filariasis afflicting millions worldwide. Here we identify new Wolbachia-disrupting compounds by conducting high-throughput cell-based chemical screens using a Wolbachia-infected, fluorescently labeled Drosophila cell line. This screen yielded several Wolbachia-disrupting compounds including three that resembled Albendazole, a widely used anthelmintic drug that targets nematode microtubules. Follow-up studies demonstrate that a common Albendazole metabolite, Albendazole sulfone, reduces intracellular Wolbachia titer both in Drosophila melanogaster and Brugia malayi, the nematode responsible for lymphatic filariasis. Significantly, Albendazole sulfone does not disrupt Drosophila microtubule organization, suggesting that this compound reduces titer through direct targeting of Wolbachia. Accordingly, both DNA staining and FtsZ immunofluorescence demonstrates that Albendazole sulfone treatment induces Wolbachia elongation, a phenotype indicative of binary fission defects. This suggests that the efficacy of Albendazole in treating filarial nematode-based diseases is attributable to dual targeting of nematode microtubules and their Wolbachia endosymbionts.
authors.affiliation: Molecular, Cell and Developmental Biology, University of California, Santa Cruz, California, USA. lrserbus@ucsc.edu
authors.forename: Laura R
authors.initials: LR
authors.lastname: Serbus
authors.forename: Frederic
authors.initials: F
authors.lastname: Landmann
authors.forename: Walter M
authors.initials: WM
authors.lastname: Bray
authors.forename: Pamela M
authors.initials: PM
authors.lastname: White
authors.forename: Jordan
authors.initials: J
authors.lastname: Ruybal
authors.forename: R Scott
authors.initials: RS
authors.lastname: Lokey
authors.forename: Alain
authors.initials: A
authors.lastname: Debec
authors.forename: William
authors.initials: W
authors.lastname: Sullivan
mesh_terms: D015766:Albendazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017178:Brugia malayi / Q000187:drug effects / Q000382:microbiology*; D002460:Cell Line; D004331:Drosophila melanogaster / Q000187:drug effects / Q000382:microbiology*; D005368:Filariasis / Q000188:drug therapy*; D008826:Microbial Sensitivity Tests; D008870:Microtubules / Q000187:drug effects; D013559:Symbiosis; D020577:Wolbachia / Q000187:drug effects*
chemical_list: C027187:albendazole sulfone; D015766:Albendazole