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Seminar Series 2008
Anti malarial activities of Centanamycin, a Novel A/T DNA-Binding agent that blocks transmission and attenuates sporozoites
| Time: Date: Venue: Presenter: |
3.00pm - 4.00pm Thursday,12 June 2008 Conference Rm, Wagga Wagga Agricultural Institute Prof Terry Spithill, School of Animal & Veterinary Sciences, Charles Sturt University, Wagga Wagga |
Most malaria treatments target the blood-stage of infection in the human host, while few can also block transmission of the parasite to the mosquito. One strategy to develop new anti-malarial drugs is to exploit the unusual proportion of adenine (A) and thymine (T) nucleotides within the Plasmodium genome. We evaluated the antimalarial activity of centanamycin that covalently binds to adenine-N3 within A/T-specific motifs and is not overtly toxic to C57/BL6 mice at doses as high as 15 mg/kg. Centanamycin is very effective against blood-stage malaria infections in vitro and in vivo and has profound effects on sexual differentiation of the parasites in mosquitoes. Following 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 detect DNA damage in parasites isolated from mice 24 h after treatment with centanamycin and importantly, this DNA damage is also detected in parasites within mosquitoes 10 days after feeding on these mice. 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. We also evaluated chemical attenuation of sporozoites as a vaccine strategy. Treatment of P. berghei sporozoites with centanamycin impaired parasite function both in vitro and in vivo . Infectivity of hepatocytes by sporozoites in vitro was significantly reduced and treated parasites showed arrested liver stage development. Inoculation of mice with sporozoites that were treated in vitro with centanamycin failed to produce blood stage infections. Furthermore, BALB/c and C57/BL6 mice vaccinated with treated sporozoites were protected against subsequent challenge with wild type sporozoites. Our findings demonstrate that chemically attenuated sporozoites could be a viable alternative for the production of an effective liver stage vaccine for malaria.
For further information about this seminar please contact:
- Prof Terry Spithill via email or tel (02) 6933 2439