title: A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro.
abstract: Lymphatic 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 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.
authors: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Sigmund-Freud Strasse 25, 53127 Bonn, Germany.
authors: Christian S
authors: CS
authors: Lentz
authors: Victoria
authors: V
authors: Halls
authors: Jeffrey S
authors: JS
authors: Hannam
authors: Björn
authors: B
authors: Niebel
authors: Uta
authors: U
authors: Strübing
authors: Günter
authors: G
authors: Mayer
authors: Achim
authors: A
authors: Hoerauf
authors: Michael
authors: M
authors: Famulok
authors: Kenneth M
authors: KM
authors: Pfarr
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004605:Elephantiasis, Filarial / Q000188:drug therapy; D005370:Filarioidea / Q000187:drug effects*; D006418:Heme / Q000096:biosynthesis*; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013559:Symbiosis; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020577:Wolbachia / Q000201:enzymology / Q000378:metabolism*
chemical_list: D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D013876:Thiophenes; C583087:wALADin1 compound; D006418:Heme; C031000:benzimidazole; D000623:Porphobilinogen Synthase; D008274:Magnesium