Journal
TROPICAL MEDICINE AND INFECTIOUS DISEASE
Volume 4, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/tropicalmed4030108
Keywords
Wolbachia; filaria; parasitic worms; Onchocerca; Brugia; drug discovery; antiwolbachial; endosymbiont; neglected tropical disease; high-throughput screening
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Funding
- Bill & Melinda Gates Foundation [OPP1107194]
- Bill and Melinda Gates Foundation [OPP1107194] Funding Source: Bill and Melinda Gates Foundation
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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.
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