On the use of inhibitors of 4-hydroxyphenylpyruvate dioxygenase as a vector-selective insecticide in the control of mosquitoes

Blood-sucking insects incorporate many times their body weight of blood in a single meal. As proteins are the major component of vertebrate blood, its digestion in the gut of hematophagous insects generates extremely high concentrations of free amino acids. Previous reports showed that the tyrosine degradation pathway plays an essential role in adapting these animals to blood feeding. Inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD), the rate-limiting step of tyrosine degradation, results in the death of insects after a blood meal. Therefore, it was suggested that compounds that block the catabolism of tyrosine could act selectively on blood-feeding insects. Here we have evaluated the toxicity against mosquitoes of three HPPD inhibitors currently used as herbicides and in human health. Among the compounds tested, nitisinone (NTBC) proved to be more potent than mesotrione (MES) and isoxaflutole (IFT) in Aedes aegypti. NTBC was lethal to Ae. aegypti in artificial feeding assays (LD50: 4.36 µM), as well as in topical application (LD50: 0.0033 nmol/mosquito). NTBC was also lethal to Ae. aegypti populations that were resistant to neurotoxic insecticides, and it was lethal to other mosquito species (Anopheles and Culex). Therefore, HPPD inhibitors, particularly NTBC, represent promising new drugs for mosquito control. Since they only affect blood-feeding organisms, they would represent a safer and more environmentally friendly alternative to conventional neurotoxic insecticides.