Evaluation of the in vitro susceptibility of various filarial nematodes to emodepside

Abstract

Filariae are vector-borne nematodes responsible for an enormous burden of disease. Human lymphatic filariasis, caused by Wuchereria bancrofti , Brugia malayi, and Brugia timori, and onchocerciasis (caused by Onchocerca volvulus ) are neglected parasitic diseases of major public health significance in tropical regions. To date, therapeutic efforts to eliminate human filariasis have been hampered by the lack of a drug with sufficient macrofilaricidal and/or long-term sterilizing effects that is suitable for use in mass drug administration (MDA) programs, particularly in areas co-endemic with Loa loa , the causative agent of loiasis. Emodepside, a semi-synthetic cyclooctadepsipeptide, has been shown to have broad-spectrum efficacy against gastrointestinal nematodes in a variety of mammalian hosts, and has been approved as an active ingredient in dewormers for cats and dogs. This paper evaluates, compares (where appropriate) and summarizes the in vitro effects of emodepside against a range of filarial nematodes at various developmental stages. Emodepside inhibited the motility of all tested stages of filariae frequently used as surrogate species for preclinical investigations ( Acanthocheilonema viteae, Brugia pahangi , Litomosoides sigmodontis , Onchocerca gutturosa , and Onchocerca lienalis ), human-pathogenic filariae ( B. malayi ) and filariae of veterinary importance ( Dirofilaria immitis ) in a concentration-dependent manner. While motility of all filariae was inhibited, both stage- and species-specific differences were observed. However, whether these differences were detected because of stage- and/or species-specific factors or as a consequence of variations in protocol parameters among the participating laboratories (such as purification of the parasites, read-out units, composition of media, incubation conditions, duration of incubation etc.) remains unclear. This study, however, clearly shows that emodepside demonstrates broad-spectrum in vitro activity against filarial nematode species across different genera and can therefore be validated as a promising candidate for the treatment of human filariases, including onchocerciasis and lymphatic filariasis.

Diethylcarbamazine mediated potentiation of emodepside induced paralysis requires TRP-2 in adult Brugia malayi

“…Emodepside has been described as a potent microfilaricide in several studies ( Kulke et al, 2014b ; Kashyap et al, 2019 ; Hübner et al, 2021 ). In an in vivo study in bovines, emodepside showed potent macrofilaricidal effects against O. ochengi ( Bah et al, 2021 ).…”

A mouse infection model and long-term lymphatic endothelium co-culture system to evaluate drugs against adult Brugia malayi

“…are more readily isolated and can survive for prolonged periods of several months, when cultured on LL-CMK2 monolayers [32]. This system, using the cattle parasite, O. gutturosa, has become adopted as the gold-standard in vitro screen to evaluate nematodicidal or anti-Wolbachia drug candidates [33][34][35][36]. However, limitations of the screen are throughput via sourcing infected cattle, mainly within Sub-Saharan Africa, and differential macrofilaricidal susceptibilities between Onchocerca and lymphatic filariae (as determined for drugs such as moxidectin and albendazole) [37][38][39][40].…”

Discovery of Ircinianin Lactones B and C—Two New Cyclic Sesterterpenes from the Marine Sponge Ircinia wistarii

“…L. sigmodontis adult female worms were isolated from chronically infected cotton rats (UKB). Three L. sigmodontis female adult worms per condition were cultured in supplemented Minimal Essential Medium (MEM) on a LLCMK2 cell layer, as previously described [ 67 ]. The positive controls consisted of doxycycline at 40, 20, 10 and 5 µM.…”