Corallopyronin A for short-course anti-wolbachial, macrofilaricidal treatment of filarial infections

Media type: E-Article
Title: Corallopyronin A for short-course anti-wolbachial, macrofilaricidal treatment of filarial infections
Contributor: Schiefer, Andrea; Hübner, 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
imprint: Public Library of Science (PLoS), 2020
Published in: PLOS Neglected Tropical Diseases
Language: English
DOI: 10.1371/journal.pntd.0008930
ISSN: 1935-2735
Keywords: Infectious Diseases ; Public Health, Environmental and Occupational Health
Origination:
Footnote:
Description: <jats:p>Current efforts to eliminate the neglected tropical diseases onchocerciasis and lymphatic filariasis, caused by the filarial nematodes <jats:italic>Onchocerca volvulus</jats:italic> and <jats:italic>Wuchereria bancrofti</jats:italic> or <jats:italic>Brugia</jats:italic> spp., respectively, are hampered by lack of a short-course macrofilaricidal–adult-worm killing–treatment. Anti-wolbachial antibiotics, e.g. doxycycline, target the essential <jats:italic>Wolbachia</jats:italic> 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-<jats:italic>Wolbachia</jats:italic> drug candidate Corallopyronin A (CorA) for <jats:italic>in vivo</jats:italic> efficacy during initial and chronic filarial infections in the <jats:italic>Litomosoides sigmodontis</jats:italic> rodent model. CorA treatment for 14 days beginning immediately after infection cleared >90% of <jats:italic>Wolbachia</jats:italic> 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 <jats:italic>Wolbachia</jats:italic> 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-<jats:italic>Wolbachia</jats:italic> 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-<jats:italic>Wolbachia</jats:italic> candidates tested in this model. In summary, CorA is a preclinical candidate for filariasis, which significantly reduces treatment times required to achieve sustained <jats:italic>Wolbachia</jats:italic> 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.</jats:p>
Access State: Open Access

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