A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits 
antifilarial activity in vitro

Lentz, C. S.; Halls, V.; Hannam, J. S.; Niebel, B.; Strübing, U.; Mayer, G.; Hoerauf, A.; Famulok, M.; Pfarr, K. M.

doi:10.1016/j.chembiol.2012.11.009

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A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro

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http://www.ncbi.nlm.nih.gov/pubmed/23438747
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引用

Lentz, C. S., Halls, V., Hannam, J. S., Niebel, B., Strübing, U., Mayer, G., Hoerauf, A., Famulok, M., & Pfarr, K. M. (2013). A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro. Chemistry & Biology, 20(2), 177-87. doi:10.1016/j.chembiol.2012.11.009.

引用: https://hdl.handle.net/11858/00-001M-0000-0028-63F6-0

要旨

Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic alpha-proteobacteria Wolbachia are essential for these parasites throughout their life cycle. Using a high-throughput chemical screen, we identified a benzimidazole compound, wALADin1, that selectively targets the delta-aminolevulinic acid dehydratase (ALAD) of Wolbachia (wALAD) and exhibits macrofilaricidal effects on Wolbachia-containing filarial worms in vitro. wALADin1 is a mixed competitive/noncompetitive inhibitor that interferes with the Mg(2+)-induced activation of wALAD. This mechanism inherently excludes activity against the Zn(2+)-dependent human ortholog and might be translatable to Mg(2+)-responsive orthologs of other bacterial or protozoan pathogens. The specificity profile of wALADin1 derivatives reveals chemical features responsible for inhibitory potency and species selectivity. Our findings validate wALADins as a basis for developing potent leads that meet current requirements for antifilarial drugs.