Monogeneans are ectoparasitic flatworms causing significant economic losses in aquaculture. This study aimed to identify potential anthelmintic agents against these parasites by integrating computer-aided drug design (CADD) and in vivo evaluation. The β-tubulin gene, a well-established anthelmintic target, was cloned from Gyrodactylus kobayashii and its three-dimensional structure was generated using homology modelling. Virtual screening of 2319 FDA-approved drugs and nine common benzimidazoles against the modelled β-tubulin identified several promising compounds with low binding energy. Subsequent in vivo anthelmintic efficacy and acute toxicity assays in goldfish revealed etravirine as a potent candidate with an EC 50 value of 0.55 mg/L and a therapeutic index (TI) greater than 18.18. This favourable safety profile highlights etravirine's potential for controlling monogenean infections in aquaculture. Flubendazole and mebendazole also demonstrated potent anthelmintic activity, with EC 50 values of 0.022 and 0.023 mg/L and therapeutic indices exceeding 45.45 and 43.48, respectively. Molecular dynamics simulations confirmed stable binding modes for flubendazole and mebendazole with β-tubulin, providing mechanistic insights into their anthelmintic activity. Overall, this study demonstrated the utility of CADD in identifying potential therapeutic agents against monogenean and underscored the importance of β-tubulin as a key target for anthelmintic therapy, contributing to the development of sustainable aquaculture practices.
Yi Li,Long Gong,Jing Wu,Wesley Hung,Mei Zhen,Shangbang Gao
Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.
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