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

Haines, Lee ORCID: https://orcid.org/0000-0001-8821-6479, Trett, Anna, Rose, Clair ORCID: https://orcid.org/0000-0001-7782-5359, Garcia, Natalia, Sterkel, Marcos, McGuinness, Dagmara, Regnault, Clément, Barrett, Michael P., Leroy, Didier, Burrows, Jeremy, Biagini, Giancarlo, Ranganath, Lakshminarayan R., Aljayyoussi, Ghaith and Acosta-Serrano, Alvaro ORCID: https://orcid.org/0000-0002-2576-7959 (2025) 'Anopheles mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone'. Science Translational Medicine, Vol 17, Issue 791.

Text Haines L et al STM 2025 Accepted MS & SM.pdf - Accepted Version Download (1MB)

Abstract

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.

Item Type:	Article
Subjects:	QX Parasitology > Insects. Other Parasites > QX 510 Mosquitoes QX Parasitology > Insects. Other Parasites > QX 515 Anopheles
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1126/scitranslmed.adr4827
Depositing User:	Rachael Kedge
Date Deposited:	28 Apr 2025 09:18
Last Modified:	28 Apr 2025 09:18
URI:	https://archive.lstmed.ac.uk/id/eprint/26638

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