wrmXpress: A modular package for high-throughput image analysis of parasitic and free-living worms

Wheeler, Nicolas J; Gallo, Kendra J.; Rehborg, Elena J. G.; Ryan, Kaetlyn T.; Chan, John D.; Zamanian, Mostafa

doi:10.1371/journal.pntd.0010937

Cited by 11 publications

(9 citation statements)

References 37 publications

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“…Videos were analyzed with the motility and segmentation modules of wrmXpress v1.3.0 54 . Videos were analyzed on a node maintained at UW-Madison’s Center for High Throughput Computing (CHTC).…”

Section: Methodsmentioning

confidence: 99%

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Multivariate chemogenomic screening prioritizes new macrofilaricidal leads

et al. 2023

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Development of direct acting macrofilaricides for the treatment of human filariases is hampered by limitations in screening throughput imposed by the parasite life cycle. In vitro adult screens typically assess single phenotypes without prior enrichment for chemicals with antifilarial potential. We developed a multivariate screen that identified dozens of compounds with submicromolar macrofilaricidal activity, achieving a hit rate of >50% by leveraging abundantly accessible microfilariae. Adult assays were multiplexed to thoroughly characterize compound activity across relevant parasite fitness traits, including neuromuscular control, fecundity, metabolism, and viability. Seventeen compounds from a diverse chemogenomic library elicited strong effects on at least one adult trait, with differential potency against microfilariae and adults. Our screen identified five compounds with high potency against adults but low potency or slow-acting microfilaricidal effects, at least one of which acts through a novel mechanism. We show that the use of microfilariae in a primary screen outperforms model nematode developmental assays and virtual screening of protein structures inferred with deep learning. These data provide new leads for drug development, and the high-content and multiplex assays set a new foundation for antifilarial discovery.

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Section: Methodsmentioning

confidence: 99%

“…Images were analyzed with the worm size module of wrmXpress 54 . Segmented worms were computationally straightened, and the length of each worm was used to measure development.…”

Section: Methodsmentioning

confidence: 99%

Multivariate chemogenomic screening prioritizes new macrofilaricidal leads

et al. 2023

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“…After acquiring the 72-h timepoint video, viability staining was performed using the CellTox Green kit (Promega); a full protocol for this procedure can also be found at the previous link. Image analysis and the subsequent measurement of optical flow and fluorescence was performed using wrmXpress v1.3.02 71 .…”

Section: Methodsmentioning

confidence: 99%

Nemacol is a small molecule inhibitor of C. elegans vesicular acetylcholine transporter with anthelmintic potential

et al. 2023

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Nematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol enhances the ability of the anthelmintic Ivermectin to paralyze C. elegans and the ruminant nematode parasite Haemonchus contortus. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through a validated anthelmintic target.

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“…Compounds that exhibited antischistosomal activity in this initial screen were then assayed at a series of decreasing concentrations to explore their structure-activity relationship. Adult S. mansoni were incubated in compound (0.1 -30 µM for 14 hours) and motility was measured using a high content imaging system and the wrmXpress pipeline to quantify worm movement (25,26). Most of these compounds were less active than MCLZ, but two compounds (MYM-V-56 and MYM-III-10) with substitutions at the C3 position retained antischistosomal activity at potency near the parent molecule MCLZ (Figure 1B&C).…”

Section: In Vitro Screen Of Meclonazepam Derivatives On Adult Schisto...mentioning

confidence: 99%

Development of non-sedating antischistosomal benzodiazepines

Mian,

Sharmin,

Mondal

et al. 2024

Preprint

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The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970's. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) are not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index, and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.

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wrmXpress: A modular package for high-throughput image analysis of parasitic and free-living worms

Cited by 11 publications

References 37 publications

Multivariate chemogenomic screening prioritizes new macrofilaricidal leads

Multivariate chemogenomic screening prioritizes new macrofilaricidal leads

Nemacol is a small molecule inhibitor of C. elegans vesicular acetylcholine transporter with anthelmintic potential

Development of non-sedating antischistosomal benzodiazepines

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