Rare disease drug can make human blood toxic to mosquitoes

The blood of people taking a drug used in the treatment of rare metabolic disorders has been found to be deadly to the malaria mosquito vector Anopheles gambiae. The researchers say the discovery could be a tool to prevent transmission of the disease in malaria-endemic areas. 

Nitisinone, a repurposed herbicide and competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), is used to treat rare human-inherited disorders affecting the body’s ability to break down the amino acid tyrosine. However, recent studies have identified that HPPD is essential for insects, such as mosquitoes, to digest their blood meals. 

In the study, the researchers found that feeding human blood containing nitisinone to female Anopheles gambiae mosquitoes was toxic to both young and old mosquitoes, as well as insecticide-resistant Anopheles strains.  

A pharmacokinetic–pharmacodynamic modelling comparison with ivermectin – an antiparasitic drug and the only human endectocide to be tested in clinical trials – showed nitisinone had improved efficacy against mosquitoes. Mosquitoes fed nitisinone died within 24 hours of blood-meal ingestion, whereas those fed ivermectin took up to four days to die.

The researchers predicted that mosquitocidal concentrations in human blood after three daily doses of nitisinone (1 mg/kg) or ivermectin (0.6 mg/kg) would last for 16 or 10 days, respectively. Although blood samples from individuals with a rare genetic metabolic disorder in the tyrosine degradation pathway, called alkaptonuria, who were taking a daily low dose of 2mg of nitisinone, were also lethal to mosquitoes. 

The researchers highlighted limitations to their study, including the safety profiles for higher doses of nitisinone and a lack of safety data from healthy populations. However, they concluded that a single dose of the drug now warrants ‘further investigation’ as a complementary intervention to prevent the transmission of malaria.