Advances in Antiwolbachial Drug Discovery for Treatment of Parasitic Filarial Worm Infections

Abstract

The intracellular bacteria now known as Wolbachia were first described in filarial worms in the 1970s, but the idea of Wolbachia being used as a macrofilaricidal target did not gain wide attention until the early 2000s, with research in filariae suggesting the requirement of worms for the endosymbiont. This new-found interest prompted the eventual organization of the Anti-Wolbachia Consortium (A-WOL) at the Liverpool School of Tropical Medicine, who, among others have been active in the field of antiwolbachial drug discovery to treat filarial infections. Clinical proof of concept studies using doxycycline demonstrated the utility of the antiwolbachial therapy, but efficacious treatments were of long duration and not safe for all infected. With the advance of robotics, automation, and high-speed computing, the search for superior antiwolbachials shifted away from smaller studies with a select number of antibiotics to high-throughput screening approaches, centered largely around cell-based phenotypic screens due to the rather limited knowledge about, and tools available to manipulate, this bacterium. A concomitant effort was put towards developing validation approaches and in vivo models supporting drug discovery efforts. In this review, we summarize the strategies behind and outcomes of recent large phenotypic screens published within the last 5 years, hit compound validation approaches and promising candidates with profiles superior to doxycycline, including ones positioned to advance into clinical trials for treatment of filarial worm infections.

Lymphatic Filariasis: An Overview

“…After mating, the females produce numerous microfilariae, which migrate into the lymphatic system and spread through the bloodstream (Fig. 5) [7,8,14,18,[23][24][25].…”

“…7), and limbs and hydrocele swelling (scrotal swelling or breast swelling) ( Fig. 8) and may develop to filarial abscesses [5,8,25,[28][29][30].…”

“…These drugs work to dispose of the larval worm, to hold the reproduction of adult worm and kill it. Some studies showed the killing of adult worm with treatment by doxycycline [5,8,22,25,29,30,35,39,40].…”

“…Diethylcarbamazine citrate (DEC) is the effectively used drug for treatment which is capable of disintegrating the adult W. bancrofti, B. malayi, and B. timori [9,25,29,30,33,35,39,40]. It rapidly disintegrates the microfilariae but disintegrates the adult worms slowly and incompletely.…”

Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models

“…Targeting Wolbachia with 4–6 weeks of doxycycline therapy leads to permanent sterilization of the adult female filariae and provides macrofilaricidal efficacy over time (~2 years) (Hoerauf et al, 2001). Since doxycycline was shown to be the first safe macrofilaricidal drug available and L. loa lacks Wolbachia endosymbionts (Büttner et al, 2003; Grobusch et al, 2003; McGarry et al, 2003; Desjardins et al, 2013), a major effort was undertaken to identify anti- Wolbachia drug candidates with an increased potency and shorter treatment regimens (Bakowski and McNamara, 2019). Quinazolines represent such a novel class of drug candidates with a potent anti- Wolbachia efficacy.…”