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 in vitro 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 in vitro 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 in vitro screening platform to quantitatively assess drug action and exclude inactive compounds from a chemical series before proceeding to in vivo 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.