Wolbachia Ferrochelatase as a potential drug target against filarial infections

Filariasis is regarded as one of the world's most disabling diseases. The disease is mainly caused by filarial nematodes; Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi, with Wuchereria bancrofti, affecting more than 150 million people in some parts of the world [1]. The infection causes inflammatory damages to the lymph and leads to the alteration of normal lymphatics to lymphedema resulting to the swelling of the limbs, breasts or genitals [2]. Although these clinical manifestations are not fatal, they tend to cause permanent disfiguration of the body and often lead to social stigma and sub-optimal mental health, loss of income-earning opportunities, and increased medical expenses for patients and their caretakers [3].

The Mass Drug Administration programme (MDA) involving treatment with ivermectin and albendazole are effective in the elimination of microfilariae (mf), but have less effect on the adult worms [4]. However, current treatment with diethylcarbamazine (DEC) has been used in some areas to reduce morbidity and transmission, and has shown to be more effective in killing the microfilariae than the adult worms, which may only be killed after prolonged treatment [5]. The action of DEC in the elimination of the microfilariae may cause unpleasant side effects that could hinder patients from completing the treatment course [6]. Although these agents are used in managing the infections, their effects are limited to mainly affecting mf but with less effect on adult filarial nematodes which can live in the human host for decades [7]. Moreover, administration of these drugs in individuals co-infected with Loa loa infection comes with some adverse complications as some develop encephalopathy and may even die when treated with DEC or ivermectin [5]. Considering the challenges associated with the current drug treatments of these filarial infections, especially those with co-infection, there is the need to discover and develop novel and improved drugs, which will help address these challenges and help alleviate cost, with the aim of eliminating filariasis as a public health problem.

These nematodes have developed a mutual symbiotic relationship with an intracellular bacteria of the genus Wolbachia, which the nematodes require for embryogenesis and survival [8]. The essential role of these intracellular bacteria in the nematode and their involvement in the pathogenesis of filariasis make Wolbachia a promising novel chemotherapeutic target for the control of filarial infections [9]. Evidently, laboratory and human clinical trials have also proven that the elimination of Wolbachia in filarial parasites by antibiotics such as doxycycline and rifampicin have suicidal effects on the adult worms as well as on the embryogenesis and development of microfilariae [10]. One of the biochemical pathways which has been identified as potentially important in the symbiotic relationship between the Wolbachia genome in B. malayi (wBm) and its nematode host is the heme biosynthesis. Heme, an iron-containing tetrapyrrole, is an essential cofactor for many proteins such as peroxidases, and catalases, which are involved in a wide range of critical biological processes, including oxidative metabolism and electron transport [11]. However, all but one heme biosynthetic gene (FC/hemH gene that encodes ferrochelatase, which catalyzes the last step in heme biosynthesis) is absent in the B. malayi genome [12], suggesting filarial nematodes are incapable of de novo heme biosynthesis, a seemingly characteristic condition of most nematodes [13]. In light of this, it can be inferred that filarial worms salvage heme intermediates from their surroundings and/or obtain them from their Wolbachia endosymbionts [7]. Heme deprivation, to a certain degree, may account for the effects caused by the elimination of wBm following antibiotic treatment of filarial worms [7]. This suggests that Wolbachia heme biosynthesis likely contributes to the survival of filarial worms and thus could be a potential anti-filarial drug target pathway [7].

We and others have previously observed that Wolbachia is a potential therapeutic platform (Hoerauf et al., 2008, Aljayyoussi et al., 2017, Kwarteng et al., 2021).The current study used Wolbachia ferrochelatase as a target to identify potential small molecule inhibitors and identified four candidates; Nilotinib, Ledipasvir, 3-benzhydryloxy-8-methyl-8-azabicyclo[3.2.1]octane, and 2-(4-Amino-piperidin-1-yl)-ethanol, as potential competitors with the enzyme's natural substrate, protoporphyrin IX (ppIX) for active pocket binding. The findings of this study may facilitate future search for alternative antifilarial drugs with improved outcomes.

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