A Cell-Based Screen Reveals that the Albendazole Metabolite, Albendazole Sulfone, Targets Wolbachia

PLoS Pathogens

Walter M. Bray¹  R. Scott Lokey¹  William Sullivan²  Laura R. Serbus²  Frederic Landmann²  Jordan Ruybal²  Pamela M. White²  Alain Debec³ 

[1] Department of Chemistry and Biochemistry, University of California, Santa Cruz, California, United States of America;Molecular, Cell and Developmental Biology, University of California, Santa Cruz, California, United States of America;Polarity and Morphogenesis Group, Jacques Monod Institute, CNRS, University Paris Diderot, UPMC Bâtiment Buffon, Paris, France

关键词: Wolbachia;    Microtubules;    Brugia malayi;    Drosophila melanogaster;    Brugia;    Nematode infections;    Oocytes;    Ovaries;   

DOI  :  10.1371/journal.ppat.1002922

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY