title: Actinoramide A Identified as a Potent Antimalarial from Titration-Based Screening of Marine Natural Product Extracts.
abstract: Methods to identify the bioactive diversity within natural product extracts (NPEs) continue to evolve. NPEs constitute complex mixtures of chemical substances varying in structure, composition, and abundance. NPEs can therefore be challenging to evaluate efficiently with high-throughput screening approaches designed to test pure substances. Here we facilitate the rapid identification and prioritization of antimalarial NPEs using a pharmacologically driven, quantitative high-throughput-screening (qHTS) paradigm. In qHTS each NPE is tested across a concentration range from which sigmoidal response, efficacy, and apparent EC50s can be used to rank order NPEs for subsequent organism reculture, extraction, and fractionation. Using an NPE library derived from diverse marine microorganisms we observed potent antimalarial activity from two Streptomyces sp. extracts identified from thousands tested using qHTS. Seven compounds were isolated from two phylogenetically related Streptomyces species: Streptomyces ballenaensis collected from Costa Rica and Streptomyces bangulaensis collected from Papua New Guinea. Among them we identified actinoramides A and B, belonging to the unusually elaborated nonproteinogenic amino-acid-containing tetrapeptide series of natural products. In addition, we characterized a series of new compounds, including an artifact, 25-epi-actinoramide A, and actinoramides D, E, and F, which are closely related biosynthetic congeners of the previously reported metabolites.
authors.affiliation: National Center of Advancing Translational Sciences, National Institutes of Health , Rockville, Maryland 20850, United States.
authors.forename: Ken Chih-Chien
authors.initials: KC
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo , Hilo, Hawaii 96720, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 240 Longwood Avenue, C-643, Boston, Massachusetts 021151, United States.
authors.forename: Shugeng
authors.initials: S
authors.lastname: Cao
authors.affiliation: Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
authors.forename: Avi
authors.initials: A
authors.lastname: Raveh
authors.affiliation: National Center of Advancing Translational Sciences, National Institutes of Health , Rockville, Maryland 20850, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: MacArthur
authors.affiliation: National Center of Advancing Translational Sciences, National Institutes of Health , Rockville, Maryland 20850, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dranchak
authors.affiliation: Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
authors.forename: George
authors.initials: G
authors.lastname: Chlipala
authors.affiliation: Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.|Departments of Medicinal Chemistry, Chemistry, and Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Okoneski
authors.affiliation: National Center of Advancing Translational Sciences, National Institutes of Health , Rockville, Maryland 20850, United States.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Guha
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20852, United States.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Eastman
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20852, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Schultz
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20852, United States.
authors.forename: Xin-Zhuan
authors.initials: XZ
authors.lastname: Su
authors.affiliation: Unidad Estrategica de Bioprospección, Instituto Nacional de Biodiversidad (INBio), Santo Domingo de Heredia, Costa Rica & CIPRONA-Escuela de Química, Universidad de Costa Rica , 2060 San Pedro, Costa Rica.
authors.forename: Giselle
authors.initials: G
authors.lastname: Tamayo-Castillo
authors.affiliation: School of Medicine and Health Sciences, University of Papua New Guinea , Boroko, Papua New Guinea.
authors.forename: Teatulohi
authors.initials: T
authors.lastname: Matainaho
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 240 Longwood Avenue, C-643, Boston, Massachusetts 021151, United States.
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.affiliation: Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.|Departments of Medicinal Chemistry, Chemistry, and Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherman
authors.affiliation: National Center of Advancing Translational Sciences, National Institutes of Health , Rockville, Maryland 20850, United States.
authors.forename: James
authors.initials: J
authors.lastname: Inglese
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D003364:Costa Rica; D019015:Geologic Sediments / Q000737:chemistry; D008386:Marine Biology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D010219:Papua New Guinea; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000187:drug effects; D013302:Streptomyces / Q000737:chemistry* / Q000235:genetics
chemical_list: C000604831:25-epi-actinoramide A; D000962:Antimalarials; D001688:Biological Products; D009842:Oligopeptides; C000604832:actinoramide A; C000604833:actinoramide B