Yeast-based high-throughput screens to identify novel compounds active against Brugia malayi

Bilsland, E., Bean, D. M., Devaney, E. and Oliver, S. G. (2016) Yeast-based high-throughput screens to identify novel compounds active against Brugia malayi. PLoS Neglected Tropical Diseases, 10(1), e0004401. (doi:10.1371/journal.pntd.0004401) (PMID:26812604) (PMCID:PMC4727890)

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Abstract

Background: Lymphatic filariasis is caused by the parasitic worms Wuchereria bancrofti, Brugia malayi or B. timori, which are transmitted via the bites from infected mosquitoes. Once in the human body, the parasites develop into adult worms in the lymphatic vessels, causing severe damage and swelling of the affected tissues. According to the World Health Organization, over 1.2 billion people in 58 countries are at risk of contracting lymphatic filariasis. Very few drugs are available to treat patients infected with these parasites, and these have low efficacy against the adult stages of the worms, which can live for 7–15 years in the human body. The requirement for annual treatment increases the risk of drug-resistant worms emerging, making it imperative to develop new drugs against these devastating diseases. Methodology/Principal Findings: We have developed a yeast-based, high-throughput screening system whereby essential yeast genes are replaced with their filarial or human counterparts. These strains are labeled with different fluorescent proteins to allow the simultaneous monitoring of strains with parasite or human genes in competition, and hence the identification of compounds that inhibit the parasite target without affecting its human ortholog. We constructed yeast strains expressing eight different Brugia malayi drug targets (as well as seven of their human counterparts), and performed medium-throughput drug screens for compounds that specifically inhibit the parasite enzymes. Using the Malaria Box collection (400 compounds), we identified nine filarial specific inhibitors and confirmed the antifilarial activity of five of these using in vitro assays against Brugia pahangi. Conclusions/Significance: We were able to functionally complement yeast deletions with eight different Brugia malayi enzymes that represent potential drug targets. We demonstrated that our yeast-based screening platform is efficient in identifying compounds that can discriminate between human and filarial enzymes. Hence, we are confident that we can extend our efforts to the construction of strains with further filarial targets (in particular for those species that cannot be cultivated in the laboratory), and perform high-throughput drug screens to identify specific inhibitors of the parasite enzymes. By establishing synergistic collaborations with researchers working directly on different parasitic worms, we aim to aid antihelmintic drug development for both human and veterinary infections.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Devaney, Professor Eileen
Authors: Bilsland, E., Bean, D. M., Devaney, E., and Oliver, S. G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:PLoS Neglected Tropical Diseases
Journal Abbr.:PLoS Negl Trop Dis
Publisher:Public Library of Science
ISSN:1935-2727
ISSN (Online):1935-2735
Copyright Holders:Copyright © 2016 Bilsland et al.
First Published:First published in PLoS Neglected Tropical Diseases 10(1): e0004401
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
649621Illuminating the darkness: exploiting IVIS imaging technologyEileen DevaneyGates Foundation (GATES)OPP1098441RI BIODIVERSITY ANIMAL HEALTH & COMPMED