Molecular mechanisms of emerging acaricide resistance in scabies mites.

Topical 5% permethrin and oral ivermectin are the current treatments of choice for scabies; however S. scabiei collected from scabies endemic communities in northern Australia show increasing tolerance to both acaricides. Particularly concerning is the documentation of ivermectin resistance in several recurrent crusted scabies patients, and increasing longitudinal tolerance of S. scabiei to ivermectin in vitro. Additionally, increased in vitro survival following permethrin exposure was observed in S. scabiei collected from patients previously exposed to permethrin compared to acaricide naïve mites. Molecular mechanisms underlying acaricide resistance in scabies may include a) alterations to target ion channels, and b) Increased drug efflux and detoxification. To this end, we have described a SNP in the voltage sensitive sodium channel gene (Vssc) associated with permethrin resistance, and identified a pH gated chloride channel and potential ivermectin target in S. scabiei. We have also demonstrated increased esterase, glutathione transferase (GST) and cytochrome P450 activity in permethrin resistant mites. The addition of the GST inhibitor diethyl maleate restored in vitro permethrin susceptibility to tolerant and resistant mites, confirming GST involvement in permethrin detoxification. Increased transcription of several GST molecules was observed in permethrin resistant S. scabiei. Similarly, mRNA levels of two GSTs and the efflux pump P-glycoprotein are significantly increased in S. scabiei collected from a recurrent crusted scabies patient over the course of ivermectin treatment. Altogether, these findings further validate multiple mechanisms of permethrin and ivermectin resistance in scabies mites, and highlight the need for development of alternative therapies for this neglected ectoparasitic disease.