A Selective Inhibitor of Heme Biosynthesis in Endosymbiotic Bacteria Elicits Antifilarial Activity In Vitro

SummaryLymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic α-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 δ-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 Mg2+-induced activation of wALAD. This mechanism inherently excludes activity against the Zn2+-dependent human ortholog and might be translatable to Mg2+-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.

► wALADin benzimidazoles are species-selective inhibitors of Wolbachia ALAD ► wALADin1 interferes with the activation of ALAD by Mg2+ ► wALADin1 has a Wolbachia-dependent macrofilaricidal effect ex vivo ► wALADins may be suitable heme biosynthesis inhibitors for other pathogens