Authors
LR Haines1; A Trett1; C Rose1; M Sterkel2; D McGuinnessC RegnaultMP BarrettD Leroy4; J Burrows4; G Biagini1; R Lakshminarayan5; G Aljayyoussi1; A Acosta-Serrano6; 1 Liverpool School of Tropical Medicine, UK; 2 Universidad de La Plata, Argentina, UK; 3 University of Glasgow , UK; 4 Medicines for Malaria Venture, Geneva, UK; 5 Royal Liverpool University Hospital, UK; 6 Department of Biological Sciences, University of Notre Dame, United States Discussion
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 to blood-feeding insects. Recent studies have identified an enzyme (4-hydroxyphenylpyruvate dioxygenase (HPPD)) that is part of the tyrosine detoxification pathway and essential for blood-feeding insect and tick survival. An FDA-approved HPPD enzyme inhibitor called nitisinone is a drug used to treat rare human inherited disorders of the tyrosine pathway. Building on the success of drug repurposing, here we demonstrate that feeding human blood containing nitisinone to the malaria-transmitting mosquito species, Anopheles gambiae, is mosquitocidal to young and old mosquitoes and insecticide-resistant strains. Proof-of-concept pharmacokinetic-pharmacodynamic (PK/PD) modelling of nitisinone's dose–exposure-response relationship, administered at the highest recommended doses for adults and children, shows improved efficacy against mosquitoes compared to the gold-standard endectocidal drug, ivermectin. In addition, blood from patients with alkaptonuria – a rare genetic metabolic disorder in the tyrosine degradation pathway – taking a daily low dose of nitisinone (2 mg), is lethal to mosquitoes. Together, these data show that inhibiting the Anopheles HPPD enzyme with nitisinone warrants further investigation as a new ectoparasitic intervention for malaria control. 
