In vivo efficacy of novel phosphoethanolamine methyltransferase inhibitors against Haemonchus contortus in a jird (Meriones unguiculatus) model

Abstract

Anthelmintic resistance (AR) presents a significant challenge to the treatment of parasites in veterinary medicine, and is emerging as a growing concern in human medicine. Despite the pressing demand for compounds with novel mechanisms of action, the introduction of new anthelmintics to the market has been scarce. In this study, we investigated the in vivo efficacy of compounds previously demonstrated to be inhibitors of phosphoethanolamine methyltransferases (PMTs), enzymes that are highly conserved among parasitic nematodes and represent a novel drug target. Inhibition of PMT enzymes disrupts phosphocholine biosynthesis, which is crucial for parasite viability. This pathway is essential to nematodes and is not present in mammals, making it an attractive and highly selective drug target. Based on previous results obtained from in vitro screenings against both drug-susceptible and multidrug-resistant (MDR) Haemonchus contortus, three candidate compounds with potent in vitro activity were selected for use in a pilot in vivo study. Here, we employed the jird (Meriones unguiculatus) – H. contortus model. The dosing regimens used were selected based on available toxicological data, but since pharmacokinetic-pharmacodynamic (PKPD) profiles of these compounds are not known, dosing regimens were not optimized. As this was a pilot study, small groups of animals were used. Relatively high reductions in worm counts were achieved, ranging from 53.5 to 72.6 %, and for two of the three compounds this reduction was statistically significant (P = 0.008, P = 0.025). These findings further support PMT enzymes as viable drug targets in parasitic nematodes and highlight the need for PKPD studies. Optimizing dosing regimens and exploring synergistic activity could enhance efficacy, advancing the development of novel anthelmintics.