Phenotypic Profiling of Macrocyclic Lactones on Parasitic Schistosoma Flatworms
Macrocyclic lactones are front-line therapies for parasitic roundworm infections; however, there are no comprehensive studies on the activity of this drug class against parasitic flatworms. Ivermectin is well known to be inactive against flatworms. However, the structure-activity relationship of mac...
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Published in | Antimicrobial agents and chemotherapy Vol. 67; no. 2; p. e0123022 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Microbiology
16.02.2023
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Subjects | |
Online Access | Get full text |
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Summary: | Macrocyclic lactones are front-line therapies for parasitic roundworm infections; however, there are no comprehensive studies on the activity of this drug class against parasitic flatworms. Ivermectin is well known to be inactive against flatworms. However, the structure-activity relationship of macrocyclic lactones may vary across phyla, and it is entirely possible other members of this drug class do in fact show antiparasitic activity on flatworms. For example, there are several reports hinting at the anti-schistosomal activity of doramectin and moxidectin. To explore this class further, we developed an automated imaging assay combined with measurement of lactate levels from worm media. This assay was applied to the screening of 21 macrocyclic lactones (avermectins, milbemycins, and others such as spinosyns) against adult schistosomes. These
assays identified several macrocyclic lactones (emamectin, milbemycin oxime, and the moxidectin metabolite 23-ketonemadectin) that caused contractile paralysis and lack of lactate production. Several of these were also active against miracidia, which infect the snail intermediate host. Hits prioritized from these
assays were administered to mice harboring patent schistosome infections. However, no reduction in worm burden was observed. Nevertheless, these data show the utility of a multiplexed
screening platform to quantitatively assess drug action and exclude inactive compounds from a chemical series before proceeding to
studies. While the prototypical macrocyclic lactone ivermectin displays minimal activity against adult Schistosoma mansoni, this family of compounds does contain schistocidal compounds which may serve as a starting point for development of new anti-flatworm chemotherapies. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors declare no conflict of interest. |
ISSN: | 0066-4804 1098-6596 1098-6596 |
DOI: | 10.1128/aac.01230-22 |