What Do Mode of Action Studies Predict for ML Resistance

The genetics of ivermectin resistance has been studied in C. elegans (Dent et al., 2000). A number of genes are known to be involved in ivermectin resistance. They include: avr-15, avr-14, glc-1, unc-7, unc-9 and dyf (dye filling defective) genes. Dent et al. (2000) have examined interactions of these genes that are required for the establishment of high levels of ivermectin resistance. They observed that simultaneous mutations of the GluCla genes avr-15, avr-14 and glc-1 were required for the establishment of high levels of immunityof more than 4000-fold. Little or no resistance is seen if there are mutations in single genes. A combination of two of the genes (avr-14 and avr-15) produced a 13-fold increase in resistance. It was also noticed that the genes unc-7 and unc-9, that encode innexins (gap junction proteins), and the dyf gene, osm-1, were connected and involved in resistance.

Figure 3.5 summarizes the information relating to the genetics of resistance to the MLs in nematodes and is derived from information mostly from C. elegans. The entry of ivermectin into the nematode is facilitated by sensory (amphidial) neurones on the head. Once the drug has gained entry across the cuticle, it is then able to interact with the GluCla receptors. There are at least three different genes encoding at least three different GluCla subunits that form inhibitory ion channels on muscle of the pharynx, motor neurones and other neurones and, in addition, perhaps on the female reproductive tract. The neurones that possess the GluCl channels connect via gap junctions that are made up of innexins, coded for by unc-7 and unc-8 genes. Thus the inhibitory effect of ivermectin on the pharynx may be direct via the GluCla2 subunit, or indirect, via the GluCla3 and GluCla1 subunits on extrapharyngeal

Fig. 3.5. Diagram showing the interaction of 'ivermectin resistance' genes. Note that the physiology and location of the target site determine how resistance genes may interact. For example, the genes unc-7 or unc-9 form gap junctions that are able to pass on potential changes (hyperpolarization) associated with stimulation of GluClal and GluCla3 subunits in inhibitory channels.

Fig. 3.5. Diagram showing the interaction of 'ivermectin resistance' genes. Note that the physiology and location of the target site determine how resistance genes may interact. For example, the genes unc-7 or unc-9 form gap junctions that are able to pass on potential changes (hyperpolarization) associated with stimulation of GluClal and GluCla3 subunits in inhibitory channels.

neurones, and require that effect to be mediated across gap junctions (unc-7 and unc-9) to the pharynx. Removal of ivermectin and other MLs from the body of nematodes appears to be mediated by P-glycoprotein excretion (Sangster, 1994). The mode of action and genetics of resistance illustrate that the development of resistance requires the simultaneous mutation of several genes to develop a high level of resistance. Factors that increase the concentration of MLs in the nematode will increase susceptibility; genes (unc-7 and unc-9) which increase the electrical effects of stimulation of the GluCl ion channel will increase susceptibility; and the presence of genes coding for GluCla subunits will increase susceptibility.

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