Repurposed Drugs That Activate Autophagy in Filarial Worms Act as Effective Macrofilaricides

• Published in: Pharmaceutics 2024-02, Vol.16 (2), p.256
• Main Authors: Voronin, Denis, Tricoche, Nancy, Peguero, Ricardo, Kaminska, Anna Maria, Ghedin, Elodie, Sakanari, Judy A, Lustigman, Sara
• Format: Article
• Language: English
• Subjects: Antibacterial agents; Antibiotics; Antibodies; Antiparasitic agents; Apoptosis; Autophagy; Bacteria; Disease transmission; Drug approval; Drugs; Ethanolamines; Females; filarial diseases; Health aspects; Infections; Ivermectin; Laboratory animals; macrofilaricidal drugs; Nematoda; Nematodes; Parasites; Proteins; repurposed drugs; Symbiosis; Tropical diseases; Wolbachia; Worms
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics16020256

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases caused by filarial nematodes that utilize insect vectors for transmission to their human hosts. Current control strategies are based on annual or biannual mass drug administration (MDA) of the drugs Ivermectin or Ivermectin plus Albendazole, respectively. These drug regimens kill the first-stage larvae of filarial worms (i.e., microfilariae) and interrupt the transmission of infections. MDA programs for these microfilaricidal drugs must be given over the lifetime of the filarial adult worms, which can reach 15 years in the case of . This is problematic because of suboptimal responses to ivermectin in various endemic regions and inefficient reduction of transmission even after decades of MDA. There is an urgent need for the development of novel alternative treatments to support the 2030 elimination goals of onchocerciasis and lymphatic filariasis. One successful approach has been to target , obligatory endosymbiotic bacteria on which filarial worms are dependent for their survival and reproduction within the human host. A 4-6-week antibiotic therapy with doxycycline, for example, resulted in the loss of that subsequently led to extensive apoptosis of somatic cells, germline, embryos, and microfilariae, as well as inhibition of fourth-stage larval development. However, this long-course regimen has limited use in MDA programs. As an alternative approach to the use of bacteriostatic antibiotics, in this study, we focused on autophagy-inducing compounds, which we hypothesized could disturb various pathways involved in the interdependency between and filarial worms. We demonstrated that several such compounds, including Niclosamide, an FDA-approved drug, Niclosamide ethanolamine (NEN), and Rottlerin, a natural product derived from Kamala trees, significantly reduced the levels of in vitro. Moreover, when these compounds were used in vivo to treat -infected gerbils, Niclosamide and NEN significantly decreased adult worm survival, reduced the release of microfilariae, and decreased embryonic development depending on the regimen and dose used. All three drugs given orally significantly reduced loads and induced an increase in levels of lysosome-associated membrane protein in worms from treated animals, suggesting that Niclosamide, NEN, and Rottlerin were effective in causing drug-induced autophagy in these filarial worms. These repurposed drugs provide a new avenue for the clearance of adul