Article

Targeting the Wolbachia Cell Division Protein FtsZ as a New Approach for Antifilarial Therapy

New York Blood Center, United States of America
PLoS Neglected Tropical Diseases (Impact Factor: 4.45). 11/2011; 5(11):e1411. DOI: 10.1371/journal.pntd.0001411
Source: PubMed

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).

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    • "Furthermore, evidence suggests that there has been TABLE 1 | Factors that contribute to the evolutionary success of Wolbachia. Scale Factors Strategies Observations Selected references Ecological timescale Vertical transmission and maintenance of infection in the individual host Correct bacterial replication -Bacterial cell-cycles in synchrony with organismal development -Evidence of functional genes involved in the bacterial cell cycle Kozek, 2005 Li et al., 2011 Avoidance of host immune system -Neither induction nor suppression of antimicrobial peptides elicited by Wolbachia -Wolbachia residence within phagosome-like structures of host origin Bourtzis et al., 2000 Cho et al., 2011 Precise bacterial localization -Preferential localization of bacteria in the oocyte during oogenesis -Utilization of microtubule-based machinery to mobilize during embryonary development Ferree et al., 2005 Toomey et al., 2013 Veneti et al., 2004 Maintenance of infection in host populations "
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    • "A notable wolbachial protein FtsZ, an analog of eukaryotic β-tubulin which is expressed in all developmental stages of B. malayi, is a GTPase, thereby making the protein an attractive drug target. Recently, berberine as a small molecule inhibitor and a natural drug identified from a highthroughput screen has been used to inhibit GTPase activity of FtsZ for combating filarial infections (Li et al. 2011). "
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    • "Quantitative PCR was performed using the DyNAmo™ HS SYBR® Green qPCR Kit (Thermo Fisher) and a CFX-96 Real Time PCR instrument (Bio-rad). To determine temporal gene expression in bacteria, quantification of the 16S rRNA is often used as a reference [31], therefore gene expression levels were calculated relative to 16S rRNA as previously described [32]. To detect expression of the intergenic region between ribA and virB8, PCR products were loaded onto a 1.2% agarose gel and stained with ethidium bromide. "
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