Evolution of Ivermectin Resistance in the Nematode Model Caenorhabditis elegans: Critical Influence of Population Size and Altered Emodepside Efficacy.

Abstract

The emergence and spread of anthelmintic resistance represent a major challenge for treating parasitic nematodes, threatening mass-drug administration control programs in humans and zoonotic hosts. Currently, experimental evidence to understand the influence of management (e.g., treatment dose and frequency) and parasite-associated factors (e.g., genetic variation, population size and mutation rates) is scarce. To rectify this knowledge gap, we performed controlled evolution experiments with the model nematode Caenorhabditis elegans and further evaluated the evolution dynamics with a computational model. Large population size was critical for rapid ivermectin resistance evolution in vitro and in silico. Male nematode production was favored during resistance evolution, suggesting a selective advantage of sexual recombination under drug pressure in vitro. Evolution of ivermectin resistance led to reduced efficacy of the structurally related anthelmintic moxidectin, as anticipated, as well as reduced efficacy of the structurally unrelated anthelmintic emodepside, which has a distinct mode of action. In contrast, albendazole, levamisole, and monepantel efficacy were not influenced by the evolution of ivermectin resistance. We conclude that combining computational modeling with in vitro evolution experiments to test specific aspects of evolution directly represents a promising approach to guide the development of novel treatment strategies to anticipate and mitigate resistance evolution in parasitic nematodes.