title: Potent antimalarial and transmission-blocking activities of centanamycin, a novel DNA-binding agent.
abstract: Most treatments for malaria target the blood stage of infection in the human host, although few can also block transmission of the parasite to the mosquito. We show here that the compound centanamycin is very effective against blood-stage malarial infections in vitro and in vivo and has profound effects on sexual differentiation of the parasites in mosquitoes. After drug treatment, parasite development is arrested within the midguts of mosquitoes, failing to produce the infective forms that migrate to the salivary glands. The mechanism of parasite death is associated with modification of Plasmodium genomic DNA. We detected DNA damage in parasites isolated from mice 24 h after treatment with centanamycin, and, importantly, we also detected this DNA damage in parasites within mosquitoes that had fed on these mice 10 days earlier. This demonstrates that damage to parasite DNA during blood-stage infection persists from the vertebrate to the mosquito host and provides a novel biochemical strategy to block malaria transmission.
authors.affiliation: Institute of Parasitology and Centre for Host-Parasite Interactions, McGill University, Ste. Anne-de-Bellevue, Quebec, Canada. s.yanow@provlab.ab.ca
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Yanow
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Purcell
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
authors.forename: Terry W
authors.initials: TW
authors.lastname: Spithill
mesh_terms: D000477:Alkylating Agents / Q000493:pharmacokinetics*; D000818:Animals; D000852:Anopheles; D000962:Antimalarials / Q000494:pharmacology*; D004195:Disease Models, Animal; D000080890:Duocarmycins; D005260:Female; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D033661:Oocysts / Q000187:drug effects; D010961:Plasmodium / Q000187:drug effects* / Q000235:genetics; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D034101:Sporozoites / Q000187:drug effects
chemical_list: D000477:Alkylating Agents; D000962:Antimalarials; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; C527858:centanamycin; C066098:duocarmycin SA