4′,6-Diamidino-2-phenylindole (DAPI) induces bundling of Escherichia coli FtsZ polymers inhibiting the GTPase activity

Nova, Esteban; Montecinos, Felipe; Brunet, Juan E.; Lagos, Rosalba; Monasterio, Octavio

doi:10.1016/j.abb.2007.06.032

Cited by 20 publications

(18 citation statements)

References 27 publications

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“…Small molecules reported to stabilize FtsZ polymers include zantrins 3 and 5 (39), ruthenium red (40) and DAPI (41), and very recently FtsZ bundling by the benzoic acid derivative OTBA (42) has been proposed as a strategy to inhibit bacterial division. It would be of interest to know whether these molecules share the PC site or bind elsewhere in FtsZ.…”

Section: Discussionmentioning

confidence: 99%

The Antibacterial Cell Division Inhibitor PC190723 Is an FtsZ Polymer-stabilizing Agent That Induces Filament Assembly and Condensation

Andreu

Schaffner-Barbero

Huecas

et al. 2010

Journal of Biological Chemistry

153

193

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Section: Discussionmentioning

confidence: 99%

The Antibacterial Cell Division Inhibitor PC190723 Is an FtsZ Polymer-stabilizing Agent That Induces Filament Assembly and Condensation

Andreu

Schaffner-Barbero

Huecas

et al. 2010

Journal of Biological Chemistry

153

193

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“…Careful scrutiny of these molecules suggests that they can be divided into seven groups based on structure and origin. For instance, 4′,6-diamidino-2-phenylindole ( 3 , DAPI), a widely used DNA dye, resembles zantrins Z5 ( 1 ) and Z2 ( 2 ) in that they all have extended heterocyclic structures that are cationic at biological pH (Figure 2A) 12, 13 . Compounds 4 8, 14 and 5 15 were designed as GTP analogs (Figure 2B).…”

Section: Introductionmentioning

confidence: 99%

Comparison of Small Molecule Inhibitors of the Bacterial Cell Division Protein FtsZ and Identification of a Reliable Cross-Species Inhibitor

et al. 2012

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FtsZ is a guanosine triphosphatase (GTPase) that mediates cytokinesis in bacteria. FtsZ is homologous in structure to eukaryotic tubulin and polymerizes in a similar head-to-tail fashion. The study of tubulin’s function in eukaryotic cells has benefited greatly from specific and potent small molecule inhibitors, including colchicine and taxol. Although many small molecule inhibitors of FtsZ have been reported, none has emerged as a generally useful probe for modulating bacterial cell division. With the goal of establishing a useful and reliable small molecule inhibitor of FtsZ, a broad biochemical cross-comparison of reported FtsZ inhibitors was undertaken. Several of these molecules, including phenolic natural products, are unselective inhibitors that seem to derive their activity from the formation of microscopic colloids or aggregates. Other compounds, including the natural product viriditoxin and the drug development candidate PC190723, exhibit no inhibition of GTPase activity using protocols in this work or under published conditions. Of the compounds studied, only zantrin Z3 exhibits good levels of inhibition, maintains activity under conditions that disrupt small molecule aggregates, and provides a platform for exploration of structure-activity relationships (SAR). Preliminary SAR studies have identified slight modifications to the two sidechains of this structure that modulate the inhibitory activity of zantrin Z3. Collectively these studies will help focus future investigations toward the establishment of probes for FtsZ that fill the roles of colchicine and taxol in studies of tubulin.

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“…Proper binary fission relies upon assembly of FtsZ filaments at the future fission site, which then leads to recruitment of numerous other factors that help stabilize and constrict the division septum [103]. ALB has been shown to suppress titer and induce filamentation of Mycobacterium tuberculosis [104], and numerous studies demonstrate that ALB-like compounds target and disrupt FtsZ in Staphylococci , Escherichia coli and M. tuberculosis [73], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115]. A role for ALB-SO2 in disrupting Wolbachia FtsZ function would be consistent with this body of work.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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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.

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4′,6-Diamidino-2-phenylindole (DAPI) induces bundling of Escherichia coli FtsZ polymers inhibiting the GTPase activity

Cited by 20 publications

References 27 publications

The Antibacterial Cell Division Inhibitor PC190723 Is an FtsZ Polymer-stabilizing Agent That Induces Filament Assembly and Condensation

The Antibacterial Cell Division Inhibitor PC190723 Is an FtsZ Polymer-stabilizing Agent That Induces Filament Assembly and Condensation

Comparison of Small Molecule Inhibitors of the Bacterial Cell Division Protein FtsZ and Identification of a Reliable Cross-Species Inhibitor

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

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