title: Chemobiosynthesis of new antimalarial macrolides.
abstract: We have synthesized new derivatives of the macrolide antibiotics erythromycin and azithromycin. Novel deoxysugar moieties were attached to these standard antibiotics by biotransformation using a heterologous host. The resulting compounds were tested against several standard laboratory and clinically isolated bacterial strains. In addition, they were also tested in vitro against standard and drug-resistant strains of human malaria parasites (Plasmodium falciparum) and the liver stages of the rodent malaria parasite (Plasmodium berghei). Antibacterial activity of modified erythromycin and azithromycin showed no improvement over the unmodified macrolides, but the modified compounds showed a 10-fold increase in effectiveness after a short-term exposure against blood stages of malaria. The new compounds also remained active against azithromycin-resistant strains of P. falciparum and inhibited growth of liver-stage parasites at concentrations similar to those used for primaquine. Our findings show that malaria parasites have two distinct responses to macrolide antibiotics, one reflecting the prokaryotic origin of the apicoplast and a second, as-yet uncharacterized response that we attribute to the eukaryotic nature of the parasite. This is the first report for macrolides that target two different functions in the Plasmodium parasites.
authors.affiliation: Microbiology Division, IBR, Instituto de Biología Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Goodman
authors.forename: Mariana
authors.initials: M
authors.lastname: Useglio
authors.forename: Salvador
authors.initials: S
authors.lastname: Peirú
authors.forename: Guillermo R
authors.initials: GR
authors.lastname: Labadie
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: McFadden
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rodríguez
authors.forename: Hugo
authors.initials: H
authors.lastname: Gramajo
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D017963:Azithromycin / Q000031:analogs & derivatives / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D004917:Erythromycin / Q000031:analogs & derivatives / Q000494:pharmacology; D018942:Macrolides / Q000138:chemical synthesis / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000962:Antimalarials; D018942:Macrolides; D004917:Erythromycin; D017963:Azithromycin; D002738:Chloroquine