Metabolomic analysis of macrocyclic lactone susceptible and resistant isolates of Dirofilaria immitis.

Resistance to macrocyclic lactone (ML) preventives in the canine heartworm Dirofilaria immitis is an emerging concern worldwide. Although ML-resistant isolates of D. immitis are genetically distinct from wildtype populations, little is known about their drug resistance mechanisms. To address this gap, we used untargeted metabolomics to characterize and compare the excreted/secreted metabolic profile of drug-susceptible Missouri (MO) and -resistant JYD-34 isolates in the presence or not of ivermectin (IVM). Both isolates showed differences in their baseline metabolomic profiles, which became substantially distinct following IVM treatment. Further analysis indicated that tryptophan metabolism (TM) was significantly different between MO and JYD-34. We identified varying enrichment profiles of metabolites linked to the kynurenine pathway (KP). Furthermore, our study suggested that IVM treatment triggers an increased release of metabolites linked to KP in MO only, suggesting a potential role of KP in modulating the host immune system.