Anopheles mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone

One approach to interrupting the transmission of insect-borne diseases that is successfully used in veterinary medicine is exploiting the ability of antiparasitic drugs to make vertebrate blood toxic for blood-feeding insects. Recent studies have identified 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme of the tyrosine detoxification pathway, as essential for hematophagous arthropods to digest their blood meals. Such blood-feeding insects include anopheline mosquitoes, which transmit malaria-causing Plasmodium parasites. A US Food and Drug Administration-approved HPPD enzyme inhibitor called nitisinone is a drug used to treat rare human-inherited disorders of the tyrosine pathway. Here, we demonstrate that feeding human blood containing nitisinone to insectary-reared female Anopheles gambiae mosquitoes was mosquitocidal to both young and old mosquitoes as well as insecticide-resistant Anopheles strains. Pharmacokinetic-pharmacodynamic (PK/PD) modeling of nitisinone's dose-response relationship (when administered at the highest recommended doses for adults and children) demonstrated improved efficacy against mosquitoes compared with the gold standard endectocidal drug, ivermectin. Furthermore, blood samples from individuals with alkaptonuria (a rare genetic metabolic disorder in the tyrosine degradation pathway), who were taking a daily low dose of 2 milligrams of nitisinone, were shown to be lethal to mosquitoes. Thus, inhibiting the Anopheles HPPD enzyme with nitisinone warrants further investigation as a complementary intervention for vector control and the prevention of malaria transmission.