title: Targeting the Wolbachia cell division protein FtsZ as a new approach for antifilarial therapy.
abstract: The use of antibiotics targeting the obligate bacterial endosymbiont Wolbachia of filarial parasites has been validated as an approach for controlling filarial infection in animals and humans. Availability of genomic sequences for the Wolbachia (wBm) present in the human filarial parasite Brugia malayi has enabled genome-wide searching for new potential drug targets. In the present study, we investigated the cell division machinery of wBm and determined that it possesses the essential cell division gene ftsZ which was expressed in all developmental stages of B. malayi examined. FtsZ is a GTPase thereby making the protein an attractive Wolbachia drug target. We described the molecular characterization and catalytic properties of Wolbachia FtsZ. We also demonstrated that the GTPase activity was inhibited by the natural product, berberine, and small molecule inhibitors identified from a high-throughput screen. Furthermore, berberine was also effective in reducing motility and reproduction in B. malayi parasites in vitro. Our results should facilitate the discovery of selective inhibitors of FtsZ as a novel anti-symbiotic approach for controlling filarial infection.  NOTE: The nucleotide sequences reported in this paper are available in GenBank™ Data Bank under the accession number wAlB-FtsZ (JN616286).
authors.affiliation: New England Biolabs, Division of Parasitology, Ipswich, Massachusetts, USA.
authors.forename: Zhiru
authors.initials: Z
authors.lastname: Li
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Garner
authors.forename: Christian
authors.initials: C
authors.lastname: Gloeckner
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
authors.forename: Clotilde K
authors.initials: CK
authors.lastname: Carlow
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001599:Berberine / Q000494:pharmacology*; D017178:Brugia malayi / Q000382:microbiology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005369:Filaricides / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D020577:Wolbachia / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D005369:Filaricides; C071525:FtsZ protein, Bacteria; D001599:Berberine; D020558:GTP Phosphohydrolases