Corallopyronin A for short-course anti-wolbachial, macrofilaricidal treatment of filarial infections.
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Authors
Schiefer, AndreaHübner, Marc P
Krome, Anna
Lämmer, Christine
Ehrens, Alexandra
Aden, Tilman
Koschel, Marianne
Neufeld, Helene
Chaverra-Muñoz, Lillibeth
Jansen, Rolf
Kehraus, Stefan
König, Gabriele M
Pogorevc, Domen
Müller, Rolf
Stadler, Marc

Hüttel, Stephan
Hesterkamp, Thomas
Wagner, Karl
Pfarr, Kenneth
Hoerauf, Achim
Issue Date
2020-12-07
Metadata
Show full item recordAbstract
Current efforts to eliminate the neglected tropical diseases onchocerciasis and lymphatic filariasis, caused by the filarial nematodes Onchocerca volvulus and Wuchereria bancrofti or Brugia spp., respectively, are hampered by lack of a short-course macrofilaricidal-adult-worm killing-treatment. Anti-wolbachial antibiotics, e.g. doxycycline, target the essential Wolbachia endosymbionts of filariae and are a safe prototype adult-worm-sterilizing and macrofilaricidal regimen, in contrast to standard treatments with ivermectin or diethylcarbamazine, which mainly target the microfilariae. However, treatment regimens of 4-5 weeks necessary for doxycycline and contraindications limit its use. Therefore, we tested the preclinical anti-Wolbachia drug candidate Corallopyronin A (CorA) for in vivo efficacy during initial and chronic filarial infections in the Litomosoides sigmodontis rodent model. CorA treatment for 14 days beginning immediately after infection cleared >90% of Wolbachia endosymbionts from filariae and prevented development into adult worms. CorA treatment of patently infected microfilaremic gerbils for 14 days with 30 mg/kg twice a day (BID) achieved a sustained reduction of >99% of Wolbachia endosymbionts from adult filariae and microfilariae, followed by complete inhibition of filarial embryogenesis resulting in clearance of microfilariae. Combined treatment of CorA and albendazole, a drug currently co-administered during mass drug administrations and previously shown to enhance efficacy of anti-Wolbachia drugs, achieved microfilarial clearance after 7 days of treatment at a lower BID dose of 10 mg/kg CorA, a Human Equivalent Dose of 1.4 mg/kg. Importantly, this combination led to a significant reduction in the adult worm burden, which has not yet been published with other anti-Wolbachia candidates tested in this model. In summary, CorA is a preclinical candidate for filariasis, which significantly reduces treatment times required to achieve sustained Wolbachia depletion, clearance of microfilariae, and inhibition of embryogenesis. In combination with albendazole, CorA is robustly macrofilaricidal after 7 days of treatment and fulfills the Target Product Profile for a macrofilaricidal drug.Citation
PLoS Negl Trop Dis. 2020 Dec 7;14(12):e0008930. doi: 10.1371/journal.pntd.0008930.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.Publisher
PLOSJournal
PLoS neglected tropical diseasesPubMed ID
33284808Type
ArticleLanguage
enEISSN
1935-2735ae974a485f413a2113503eed53cd6c53
10.1371/journal.pntd.0008930
Scopus Count
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- Creative Commons
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