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J Nat Prod. 2015 Oct 23;78(10):2411-22. doi: 10.1021/acs.jnatprod.5b00489. Epub 2015 Oct 14.

Actinoramide A Identified as a Potent Antimalarial from Titration-Based Screening of Marine Natural Product Extracts.

Author information

1
National Center of Advancing Translational Sciences, National Institutes of Health , Rockville, Maryland 20850, United States.
2
Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo , Hilo, Hawaii 96720, United States.
3
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 240 Longwood Avenue, C-643, Boston, Massachusetts 021151, United States.
4
Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
5
Departments of Medicinal Chemistry, Chemistry, and Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
6
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20852, United States.
7
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.
8
School of Medicine and Health Sciences, University of Papua New Guinea , Boroko, Papua New Guinea.

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.

PMID:
26465675
PMCID:
PMC4633019
DOI:
10.1021/acs.jnatprod.5b00489
[Indexed for MEDLINE]
Free PMC Article

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