title: A Malaria Transmission-Blocking (+)-Usnic Acid Derivative Prevents Plasmodium Zygote-to-Ookinete Maturation in the Mosquito Midgut.
abstract: The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence of artemisinin resistance in Southeast Asia underscores the need to develop novel antimalarials and identify new targetable pathways in Plasmodium parasites. Transmission-blocking approaches, which typically target gametocytes in the host bloodstream or parasite stages in the mosquito gut, are recognized collectively as a strategy that when used in combination with antimalarials that target erythrocytic stages will not only cure malaria but will also prevent subsequent transmission. We tested four derivatives of (+)-usnic acid, a metabolite isolated from lichens, for transmission-blocking activity against Plasmodium falciparum using the standard membrane feeding assay. For two of the derivatives, BT37 and BT122, we observed a consistent dose-response relationship between concentration in the blood meal and oocyst intensity in the midgut. To explore their mechanism of action, we used the murine model Plasmodium berghei and found that both derivatives prevent ookinete maturation. Using fluorescence microscopy, we demonstrated that in the presence of each compound zygote vitality was severely affected, and those that did survive failed to elongate and mature into ookinetes. The observed phenotypes were similar to those described for mutants of specific kinases (NEK2/NEK4) and of inner membrane complex 1 (IMC1) proteins, which are all vital to the zygote-to-ookinete transition. We discuss the implications of our findings and our high-throughput screening approach to identifying next generation, transmission-blocking antimalarials based on the scaffolds of these (+)-usnic acid derivatives.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pastrana-Mena
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, United States.
authors.forename: Derrick K
authors.initials: DK
authors.lastname: Mathias
authors.affiliation: Department of Life Sciences, Imperial College of London , London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Delves
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, United States.
authors.forename: Krithika
authors.initials: K
authors.lastname: Rajaram
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, United States.
authors.forename: Jonas G
authors.identifier: 0000-0003-2270-4212
authors.initials: JG
authors.lastname: King
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Yee
authors.affiliation: Department of Chemistry, University of Milan , Milan, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Trucchi
authors.affiliation: Department of Chemistry, University of Milan , Milan, Italy.
authors.forename: Luisella
authors.initials: L
authors.lastname: Verotta
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, United States.
authors.forename: Rhoel R
authors.identifier: 0000-0001-5433-8179
authors.initials: RR
authors.lastname: Dinglasan
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology*; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery; D005260:Female; D007303:Insect Vectors / Q000469:parasitology; D008288:Malaria / Q000517:prevention & control* / Q000635:transmission*; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D051381:Rats; D015053:Zygote / Q000187:drug effects / Q000254:growth & development
chemical_list: D000962:Antimalarials; D001572:Benzofurans; C073339:usnic acid