Novel inhibitors of the renal inward rectifier potassium (Kir) channel of the mosquito vector Aedes aegypti

The mosquito continues to be the most lethal animal to humans due to the devastating diseases that it carries and transmits. Controlling mosquito-borne diseases relies heavily on vector management using neurotoxic insecticides with limited modes of action. This has led to the emergence of resistance to pyrethroids and other neurotoxic insecticides in mosquitoes, which has reduced the efficacy of chemical control agents. Moreover, many neurotoxic insecticides are not selective for mosquitoes and negatively impact beneficial insects such as honeybees. Developing new mosquitocides with novel mechanisms of action is a clear unmet medical need; this review covers the efforts made toward this end by targeting the renal inward rectifier potassium channel (Kir) of the mosquito.

EFFICACY OF CHITIN SYNTHESIS INHIBITORS IN ARRESTING GROWTH AND DEVELOPMENT OF OKRA JASSID, AMRASCA BIGUTTULA BIGUTTULA (ISHIDA)

Chitin synthesis inhibitors (CSIs) are potential inhibitory chemical compound that disrupt molting process by interfering chitin synthesis and kill insects before attaining maturity. In this study, some chitin synthesis inhibitors (CSIs) viz. Tacoma 40SC (Buprofezin), Heron 5EC (Lufenuron), Pyrifen 10.8EC (Pyriproxifen) and Chitosan 75WP were tested against okra jassid, Amrasca biguttula biguttula (Ishida) to elucidate their potential effects in arresting body growth and development. The nymphs of jassids were exposed to selected CSIs through different application methods like topical, leaf-dip and the combination of both topical and leaf-dip. Weight data was collected at 7 days after treatment (DAT) application. Results showed that all of the CSIs except Chitosan had significant effect on the body weight reduction of okra jassid. Growth reduction was clearly concentrations and application method dependent. It has shown that higher concentrations were found to be more effective than lower concentrations. Bioassay study has showed that all the selected CSIs became able to enter in the insect body through contact as well as stomach action to disrupt molting process by inhibiting chitin synthesis that confirmed the contact and systemic actions of the selected CSIs. This study recommends that Tacoma 40SC @ 1.0 ml/L, Heron 5EC @ 1.5 ml/L and Pyrifen 10.8 EC @ 1.5 ml/L may be the potential alternatives of conventional neurotoxic insecticides in controlling jassids as they reduced 50-60% weight compared to untreated control. Moreover, protocols developed in this study for jassids collection and their safe transferring inside the petri dishes would be a useful and convenient approach for the researchers.

Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce populations of insect pollinator species. Here we present a promising, environment-friendly alternative to current insecticides that targets the insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded and eliminated. RNA interference (RNAi) of either the first two enzymes in the tyrosine degradation pathway (tyrosine aminotransferase (TAT) and 4-hydroxyphenylpyruvate dioxygenase (HPPD)) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, oral administration of NTBC to bumblebees did not affect their survival. Using a novel mathematical model, we show that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current disease elimination programmes.

Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis

Tsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce insect pollinator species. Here we present a promising, environment-friendly alternative that targets insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded. RNAi silencing of either the first two enzymes in the tyrosine degradation pathway (TAT and HPPD) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, it did not affect bumblebee survival. A mathematical model shows that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current elimination programmes.

Enzymatic detoxification strategies for neurotoxic insecticides in adults of three tortricid pests

We examined the role of the most important metabolic enzyme families in the detoxification of neurotoxic insecticides on adult males and females from susceptible populations of Cydia pomonella (L.), Grapholita molesta (Busck), and Lobesia botrana (Denis & Schiffermüller). The interaction between the enzyme families – carboxylesterases (EST), glutathione-S-transferases (GST), and polysubstrate monooxygenases (PSMO) – with the insecticides – chlorpyrifos, λ-cyhalothrin, and thiacloprid – was studied. Insect mortality arising from the insecticides, with the application of enzyme inhibitors – S,S,S-tributyl phosphorotrithioate (DEF), diethyl maleate (DEM), and piperonyl butoxide (PBO) – was first determined. The inhibitors' influence on EST, GST, and PSMO activity was quantified. EST and PSMO (the phase-I enzymatic activities) were involved in the insecticide detoxification in the three species for both sexes, highlighting the role of EST, whereas GST (phase-II enzymes) was involved only in G. molesta insecticide detoxification. L. botrana exhibited, in general, the highest level of enzymatic activity, with a significantly higher EST activity compared with the other species. It was the only species with differences in the response between sexes, with higher GST and PSMO activity in females than in males, which can be explained as the lower susceptibility of the females to the tested insecticides. A positive correlation between PSMO activity and the thiacloprid LD50s in the different species-sex groups was observed explaining the species-specific differences in susceptibility to the product reported in a previous study.

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.Author SummaryThe control of mosquitoes has been pursued in the last decades by the use of neurotoxic insecticides to prevent the spreading of dengue, zika and malaria, among other diseases. However, the selection and propagation of different mechanisms of resistance hinder the success of these compounds. New methodologies are needed for their control. Hematophagous arthropods, including mosquitoes, ingest quantities of blood that represent many times their body weight in a single meal, releasing huge amounts of amino acids during digestion. Recent studies showed that inhibition of the tyrosine catabolism pathway could be a new selective target for vector control. Thus we tested three different inhibitors of the second enzyme in the tyrosine degradation pathway as tools for mosquito control. Results showed that Nitisinone (NTBC), an inhibitor used in medicine, was the most potent of them. NTBC was lethal to Aedes aegypti when it was administered together with the blood meal and when it was topically applied. It also caused the death of Anopheles aquasalis and Culex quinquefasciatus mosquitoes, as well as field-collected Aedes populations resistant to neurotoxic insecticides, indicating that there is no cross-resistance. We discuss the possible use of NTBC as a new insecticide.

Physically acting products for head lice – the end of the beginning

Treatment of head louse infestation has evolved from widespread use of neurotoxic insecticides that have been extensively affected by resistance since the mid-1990s into the use of so-called physically acting treatments. It is widely believed that physically acting products are effectively “resistance proofed” because they do not act to inhibit any particular physiological mechanism and most have some kind of occlusive effect on the target organism. Over the past 20 years various new active materials have been utilized ranging from natural oils, synthetic oils, through to surfactants both as excipients and active substances. Relatively few of these products have been adequately tested clinically and, of those that have, there is now some indication that they are less effective than when first introduced. The question therefore arises whether lice can become resistant to these physically acting products. Only adequate testing both in the laboratory and in clinical trials can determine their real effectiveness and claiming efficacy based on the presence of a named chemical rather than demonstrated activity may result in acquired resistance to these types of product also.

Physically acting products for head lice – the end of the beginning

Treatment of head louse infestation has evolved from widespread use of neurotoxic insecticides that have been extensively affected by resistance since the mid-1990s into the use of so-called physically acting treatments. It is widely believed that physically acting products are effectively “resistance proofed” because they do not act to inhibit any particular physiological mechanism and most have some kind of occlusive effect on the target organism. Over the past 20 years various new active materials have been utilized ranging from natural oils, synthetic oils, through to surfactants both as excipients and active substances. Relatively few of these products have been adequately tested clinically and, of those that have, there is now some indication that they are less effective than when first introduced. The question therefore arises whether lice can become resistant to these physically acting products. Only adequate testing both in the laboratory and in clinical trials can determine their real effectiveness and claiming efficacy based on the presence of a named chemical rather than demonstrated activity may result in acquired resistance to these types of product also.