55 Papers found (0.01 seconds)

Burns AR et al. (2015) Nat Commun "Caenorhabditis elegans is a useful model for anthelmintic discovery."

[

Nat Commun,

2015]

Parasitic nematodes infect one quarter of the world's population and impact all humans through widespread infection of crops and livestock. Resistance to current anthelmintics has prompted the search for new drugs. Traditional screens that rely on parasitic worms are costly and labour intensive and target-based approaches have failed to yield novel anthelmintics. Here, we present our screen of 67,012 compounds to identify those that kill the non-parasitic nematode Caenorhabditis elegans. We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules. Genetic screens of 19 million C. elegans mutants reveal those nematicides for which the generation of resistance is and is not likely. We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain. This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery.

Burns AR et al. (2023) Nature "Selective control of parasitic nematodes using bioactivated nematicides."

[

Nature,

2023]

Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amid limited arable land<sup>1-4</sup>. Most traditional nematicides have been banned owing to poor nematode selectivity, leaving farmers with inadequate means of pest control<sup>4-12</sup>. Here we use the model nematode Caenorhabditis elegans to identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome-p450-mediated bioactivation in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita, a highly destructive plant-parasitic nematode. Tests against numerous phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than most marketed nematicides. Selectivins are first-in-class bioactivated nematode controls that provide efficacy and nematode selectivity.

Burns AR et al. (2010) Nat Chem Biol "A predictive model for drug bioaccumulation and bioactivity in Caenorhabditis elegans."

Cutler SR, Roy PJ, Bader GD, Wildenhain J, Tyers M, Burns AR, Giaever G, Nislow C, Wallace IM

[

Nat Chem Biol,

2010]

The resistance of Caenorhabditis elegans to pharmacological perturbation limits its use as a screening tool for novel small bioactive molecules. One strategy to improve the hit rate of small-molecule screens is to preselect molecules that have an increased likelihood of reaching their target in the worm. To learn which structures evade the worm's defenses, we performed the first survey of the accumulation and metabolism of over 1,000 commercially available drug-like small molecules in the worm. We discovered that fewer than 10% of these molecules accumulate to concentrations greater than 50% of that present in the worm's environment. Using our dataset, we developed a structure-based accumulation model that identifies compounds with an increased likelihood of bioavailability and bioactivity, and we describe structural features that facilitate small-molecule accumulation in the worm. Preselecting molecules that are more likely to reach a target by first applying our model to the tens of millions of commercially available compounds will undoubtedly increase the success of future small-molecule screens with C. elegans.

Burns AR et al. (2020) Nat Commun "Author Correction: Caenorhabditis elegans is a useful model for anthelmintic discovery."

[

Nat Commun,

2020]

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Burns AR et al. (2017) PLoS Negl Trop Dis "The novel nematicide wact-86 interacts with aldicarb to kill nematodes."

Roy PJ, Burns AR, Yeo M, Schertzberg M, Fraser AG, Luciani GM, Bagg R

[

PLoS Negl Trop Dis,

2017]

Parasitic nematodes negatively impact human and animal health worldwide. The market withdrawal of nematicidal agents due to unfavourable toxicities has limited the available treatment options. In principle, co-administering nematicides at lower doses along with molecules that potentiate their activity could mitigate adverse toxicities without compromising efficacy. Here, we screened for new small molecules that interact with aldicarb, which is a highly effective treatment for plant-parasitic nematodes whose toxicity hampers its utility. From our collection of 638 worm-bioactive compounds, we identified 20 molecules that interact positively with aldicarb to either kill or arrest the growth of the model nematode Caenorhabditis elegans. We investigated the mechanism of interaction between aldicarb and one of these novel nematicides called wact-86. We found that the carboxylesterase enzyme GES-1 hydrolyzes wact-86, and that the interaction is manifested by aldicarb's inhibition of wact-86's metabolism by GES-1. This work demonstrates the utility of C. elegans as a platform to search for new molecules that can positively interact with industrial nematicides, and provides proof-of-concept for prospective discovery efforts.

Burns AR et al. (2006) Nat Protoc "High-throughput screening of small molecules for bioactivity and target identification in Caenorhabditis elegans."

Burns AR, Roy PJ, Kwok TC, Chan A, Howard A, Johanson K, Cutler SR, McCourt P, Houston E

[

Nat Protoc,

2006]

This protocol describes a procedure for screening small molecules for bioactivity and a genetic approach to target identification using the nematode Caenorhabditis elegans as a model system. Libraries of small molecules are screened in 24-well plates that contain a solid agar substrate. On top of the agar mixture, one small-molecule species is deposited into each well, along with worm food (E. coli), and two third-stage or fourth-stage larval worms using a COPAS (Complex Object Parametric Analyzer and Sorter) Biosort. Three to five days later the plates are screened for phenotype. Images of the wells are acquired and archived using a HiDI 2100 automated imaging system (Elegenics). Up to 2,400 chemicals can be screened per week. To identify the predicted protein target of a bioactive molecule, wild-type worms are mutagenized using ethylmethanesulfonate (EMS). Progeny are screened for individuals resistant to the molecules effects. The candidate mutant target that confers resistance is then identified. Target identification might take months.

Furuhashi T et al. (2016) Biochem Biophys Res Commun "L-arginine, an active component of salmon milt nucleoprotein, promotes thermotolerance via Sirtuin in Caenorhabditis elegans."

Furuhashi T, Matsunaga M, Sakamoto K, Asahara Y

[

Biochem Biophys Res Commun,

2016]

We previously showed that salmon milt nucleoprotein (NP) promotes thermotolerance in Caenorhabditis elegans; however, the active component and physiological mechanism of this effect has remained unclear. l-arginine (AR) is a major component of protamine and thus it has been proposed as the possible active component of NP. In this study, the viability of C. elegans treated with AR under heat stress was assessed and AR was shown to extend the survival term of the heat-stressed organisms. Additionally, AR was shown to restore the thrashing movement of the worms that is suppressed by heat stress. Treatment with AR was furthermore shown to promote thermotolerance in a DAF-16- and SIR-2.1-dependent manner, where DAF-16 and SIR-2.1 are homologs of FoxO and SirT1, respectively. Taken together, these data suggest that AR is one of the active components of NP and promotes thermotolerance via the activation of DAF-16 and SIR-2.1.

Toshiaki Suzuki et al. (2003) International Worm Meeting "Analysis of Ce-PARKIN in C. elegans"

Nobutaka Hattori, Toshiaki Suzuki, Keiji Tanaka, Yoshikuni Mizuno, Shohei MItani, Noriyuki Matsuda, Hideki Yashiroda, Toshiaki Kitami, Keiko Gengyo-Ando

[

International Worm Meeting,

2003]

Autosomal recessive juvenile parkinsonism (AR-JP) is one of the most common forms of familial parkinsons disease characterized by selective loss of dopaminergic neurons in substantia nigra and the locus coeruleus. parkin is the causative gene of AR-JP. The human parkin gene encodes 465 amino acids with a ubiquitin-like domain in the amino-terminus and two RING finger motifs in the carboxy terminus. So far, various deletion mutations and point mutations have been discovered in patients of AR-JP, suggesting that the loss of function of Parkin is the cause of AR-JP. Recently we and others showed that Parkin has a ubiquitin-protein ligase activity and therefore suggested that the defect of protein degradation in the neurons of AR-JP patients (Shimura H. et al. Nat. Genet. 25, 302-5, 2000). To investigate the function of Parkin in vivo, we began to analyze the Ce-PARKIN of C. elegans. Two deletion mutations in parkin genes show no defect in their viabilities. The expression of Ce-PARKIN seems to be specific to subset of neurons. Therefore, we focused on the function of Ce-PARKIN in the neurons and the analysis is underway.

Partridge, Frederick A. et al. (2011) International Worm Meeting "Identification and validation of C. elegans permeability mutants as a tool for drug screening and chemical genetics."

Sattelle, David B., Hodgkin, Jonathan, Youdell, Michael L., Darby, Creg, O'Rourke, Delia, Stroud, Dave, Partridge, Frederick A., Buckingham, Steven D.

[

International Worm Meeting,

2011]

C. elegans is growing in importance as an in vivo screening tool for new drugs. It can be engineered to mimic human disease mutations, and is the only organism in which thousands of candidate compounds can be screened in a high-throughput whole animal model. This is particularly important for complex multi-tissue disease. Unfortunately, less than 10% of human orally bioavailable drug compounds accumulate in C. elegans [1]. This greatly limits the chances of drug discovery using the worm. Mutants that increase permeability could therefore be useful. We previously identified mutants in bus-8 that are permeable, but these have additional confounding phenotypes including lethality that limit their use for drug screening [2]. Mutations in a least six other genes can result in increased cuticle permeability. Here we present the identification and utilization of a new gene, bus-5, which encodes a predicted NAD+-dependent epimerase. Some alleles of bus-5 show greatly increased permeability with few background phenotypes. We are validating the increased permeability of these mutants by directly measuring accumulation via an HPLC-based approach. We also present proof-of-principle drug screens combining our permeability mutants with existing disease model strains. For these screens we make use of a automated thrashing assay that allows thousands of compounds to be easily screened per day [3]. Permeability mutants are also an important tool for the community as they allow the use of small-molecule inhibitors and other molecular tools that were previously unavailable to C. elegans researchers due to poor uptake. [1] Burns AR et al, 2010. Nat. Chem. Biol. 6 549 [2] Partridge FA et al, 2008. Dev. Biol. 317 549 [3] Sleigh JN et al, 2011. Hum. Mol. Genet. 20 245.

Hart EH et al. (2015) Vet Parasitol "A new enabling proteomics methodology to investigate membrane associated proteins from parasitic nematodes: case study using ivermectin resistant and ivermectin susceptible isolates of Caenorhabditis elegans and Haemonchus contortus."

Brophy PM, Wolf BT, Prescott M, Hart EH, Hamilton JV, Bartley DJ

[

Vet Parasitol,

2015]

The mechanisms involved in anthelmintic resistance (AR) are complex but a greater understanding of AR management is essential for effective and sustainable control of parasitic helminth worms in livestock. Current tests to measure AR are time consuming and can be technically problematic, gold standard diagnostics are therefore urgently required to assist in combatting the threat from drug resistant parasites. For anthelmintics such as ivermectin (IVM), target proteins may be present in the cellular membrane. As proteins usually act in complexes and not in isolation, AR may develop and be measurable in the target associated proteins present in the parasite membrane. The model nematode Caenorhabditis elegans was used to develop a sub-proteomic assay to measure protein expression differences, between IVM resistant and IVM susceptible isolates in the presence and absence of drug challenge. Evaluation of detergents including CHAPS, ASB-14, C7BzO, Triton x100 and TBP (tributyl phosphine) determined optimal conditions for the resolution of membrane proteins in Two Dimensional Gel Electrophoresis (2DE). These sub-proteomic methodologies were then translated and evaluated using IVM-susceptible and IVM-resistant Haemonchus contortus; a pathogenic blood feeding parasitic nematode which is of global importance in livestock health, welfare and productivity. We have demonstrated the successful resolution of membrane associated proteins from both C. elegans and H. contortus isolates, using a combination of CHAPS and the zwitterionic amphiphilic surfactant ASB-14 to further support the detection of markers for AR.

load 10 more results