title: High-throughput screening platform for natural product-based drug discovery against 3 neglected tropical diseases: human African trypanosomiasis, leishmaniasis, and Chagas disease.
abstract: African trypanosomiasis, leishmaniasis, and Chagas disease are 3 neglected tropical diseases for which current therapeutic interventions are inadequate or toxic. There is an urgent need to find new lead compounds against these diseases. Most drug discovery strategies rely on high-throughput screening (HTS) of synthetic chemical libraries using phenotypic and target-based approaches. Combinatorial chemistry libraries contain hundreds of thousands of compounds; however, they lack the structural diversity required to find entirely novel chemotypes. Natural products, in contrast, are a highly underexplored pool of unique chemical diversity that can serve as excellent templates for the synthesis of novel, biologically active molecules. We report here a validated HTS platform for the screening of microbial extracts against the 3 diseases. We have used this platform in a pilot project to screen a subset (5976) of microbial extracts from the MEDINA Natural Products library. Tandem liquid chromatography-mass spectrometry showed that 48 extracts contain potentially new compounds that are currently undergoing de-replication for future isolation and characterization. Known active components included actinomycin D, bafilomycin B1, chromomycin A3, echinomycin, hygrolidin, and nonactins, among others. The report here is, to our knowledge, the first HTS of microbial natural product extracts against the above-mentioned kinetoplastid parasites.
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: F
authors.initials: F
authors.lastname: Annang
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: G
authors.initials: G
authors.lastname: Pérez-Moreno
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: R
authors.initials: R
authors.lastname: García-Hernández
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: C
authors.initials: C
authors.lastname: Cordon-Obras
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: J
authors.initials: J
authors.lastname: Martín
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: J R
authors.initials: JR
authors.lastname: Tormo
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: L
authors.initials: L
authors.lastname: Rodríguez
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: N
authors.initials: N
authors.lastname: de Pedro
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: V
authors.initials: V
authors.lastname: Gómez-Pérez
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: M
authors.initials: M
authors.lastname: Valente
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: F
authors.initials: F
authors.lastname: Reyes
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: O
authors.initials: O
authors.lastname: Genilloud
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: F
authors.initials: F
authors.lastname: Vicente
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: S
authors.initials: S
authors.lastname: Castanys
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: L M
authors.initials: LM
authors.lastname: Ruiz-Pérez
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: M
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain.
authors.forename: F
authors.initials: F
authors.lastname: Gamarro
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain dgonzalez@ipb.csic.es.
authors.forename: D
authors.initials: D
authors.lastname: González-Pacanowska
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001688:Biological Products / Q000494:pharmacology* / Q000627:therapeutic use; D014355:Chagas Disease / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods* / Q000592:standards; D057166:High-Throughput Screening Assays / Q000379:methods* / Q000592:standards; D006801:Humans; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy; D058069:Neglected Diseases / Q000188:drug therapy; D014347:Trypanosoma brucei gambiense / Q000187:drug effects*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D000981:Antiprotozoal Agents; D001688:Biological Products
keywords: Chagas disease; high-throughput screening; human African trypanosomiasis; kinetoplastids; leishmaniasis; microbial extracts; natural products; tropical diseases