title: Salinipostins A-K, long-chain bicyclic phosphotriesters as a potent and selective antimalarial chemotype.
abstract: Despite significant advances in antimalarial chemotherapy over the past 30 years, development of resistance to frontline drugs remains a significant challenge that limits efforts to eradicate the disease. We now report the discovery of a new class of antimalarials, salinipostins A-K, with low nanomolar potencies and high selectivity indices against mammalian cells (salinipostin A: Plasmodium falciparum EC50 50 nM, HEK293T cytotoxicity EC50 > 50 μM). These compounds were isolated from a marine-derived Salinospora sp. bacterium and contain a bicyclic phosphotriester core structure, which is a rare motif among natural products. This scaffold differs significantly from the structures of known antimalarial compounds and represents a new lead structure for the development of therapeutic targets in malaria. Examination of the growth stage specificity of salinipostin A indicates that it exhibits growth stage-specific effects that differ from compounds that inhibit heme polymerization, while resistance selection experiments were unable to identify parasite populations that exhibited significant resistance against this compound class.
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schulze
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarro
authors.forename: Daniel
authors.initials: D
authors.lastname: Ebert
authors.forename: Joseph
authors.initials: J
authors.lastname: DeRisi
authors.forename: Roger G
authors.initials: RG
authors.lastname: Linington
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D057809:HEK293 Cells / Q000737:chemistry*; D006801:Humans; D008288:Malaria / Q000378:metabolism*; D008386:Marine Biology; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D001688:Biological Products; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C000600212:salinipostin A