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.NoteThe nucleotide sequences reported in this paper are available in GenBank™ Data Bank under the accession number wAlB-FtsZ (JN616286).
Highlights
Filarial nematode parasites are responsible for a number of devastating diseases in humans and animals
We have investigated the cell division process in Wolbachia for new drug target discovery
We describe the molecular characterization and catalytic properties of the enzyme and demonstrate that the GTPase activity is inhibited by the natural product, berberine, and small molecule inhibitors identified from a high-throughput screen
Summary
Filarial nematode parasites are responsible for a number of devastating diseases in humans and animals. Their presence is essential for the worm, as tetracyclinemediated clearance of bacteria from Brugia spp. leads to developmental arrest in immature stages and reduction in adult worm fertility and viability [5,6,7,8,9,10] These findings have pioneered the approach of using antibiotics to treat and control filarial infections. The completed genome sequence of the Wolbachia endosymbiont of B. malayi (wBm) [11] enables genome-wide mining for new drug targets [11,12,13,14] and a foundation for rational drug design These approaches should lead to the discovery of new classes of compounds with potent anti-Wolbachia/antifilarial activities targeting essential processes that are absent or substantially different in the mammalian host
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