Identifying Genetic Markers and Molecular Pathways Underlying Emerging Anthelmintic Resistance in Human Helminths

Abstract

Helminth infections remain a major cause of morbidity in low- and middle-income regions, despite decades of large-scale preventive chemotherapy programs. Current control strategies rely heavily on a limited number of anthelmintic drug classes: benzimidazoles, macrocyclic lactones, and cholinergic agonists administered repeatedly through mass drug administration (MDA). This sustained reliance has increased selective pressure on parasite populations, raising growing concern about the emergence of drug resistance that could undermine long-term program effectiveness. While anthelmintic resistance is well documented in veterinary helminths, molecular evidence in human parasites remains fragmented and under characterized. This review provides an integrative, human-helminth–focused synthesis of current knowledge on genetic markers and molecular pathways associated with emerging anthelmintic resistance. We summarize evidence for β-tubulin polymorphisms linked to benzimidazole resistance, alterations in ligand-gated ion channels affecting macrocyclic lactone sensitivity, and the upregulation of efflux transporter systems that contribute to multidrug tolerance. We also examine transcriptomic, metabolic, and regulatory pathways—including detoxification networks and epigenetic modifications that may stabilize resistance phenotypes and offset associated fitness costs. Advances in genomics, population genetics, and functional approaches are accelerating the detection of resistance signals, although standardized molecular surveillance frameworks for human helminths remain limited. We discuss the public health implications of these findings, highlight vulnerabilities in MDA-based control programs, and outline future strategies—including molecular diagnostics, combination therapies, and genomic surveillance—to support sustainable helminth control and guide anthelmintic development.