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Publications

Journal Article Ppublish

PubMed: 42619137 DOI: 10.1021/jacs.6c11333

Discovery of Sphaeriaurantins as Rapid-Acting Antiplasmodials with Dual Activity in Blood and Liver Stages.

J Am Chem Soc 148(32):35017-35030

Authors: Chantal D Bader, Jennifer E Collins, Yuelan Li, Edward Kalkreuter, Jasveen Bhasin, Mariana Laureano De Souza, Raphaella A Paes Lopez, Jin H Jeon, Nonlawat Boonyalai, Chun Gui, Dong Yang, David A Fidock, Marcus C S Lee, Elizabeth A Winzeler, Debopam Chakrabarti, Ben Shen

Affiliations

  • Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida33458, United States.
  • Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida32826, United States.
  • Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California92093, United States.
  • Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York10032, United States.
  • Biological Chemistry and Drug Discovery, Faculty of Life Sciences, University of Dundee, DundeeDD14HN, U.K.
  • Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida33458, United States. Natural Products Discovery Center, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida33458, United States.
  • Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida33458, United States. Natural Products Discovery Center, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida33458, United States. Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida33458, United States. Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, Jupiter, Florida33458, United States.

Abstract

The rapid emergence of resistance in the malaria-causing protozoan Plasmodium falciparum has heightened the demand for treatments with novel modes of action. Having evolved to produce a myriad of structurally diverse natural products (NPs) as defenses against soil-dwelling parasites including protozoa, Actinomycetota strains are a promising source for the discovery of NPs as antiplasmodial drug leads. Herein, the selective inhibition of P. falciparum is reported for five distinct NP families from Actinomycetota, including an unprecedented family of glycosylated type II polyketides termed sphaeriaurantins (SPAs). The structures of SPAs were established through the combination of MS and NMR spectroscopic data analysis, derivatization and comparison of the deoxyhexose moieties to authentic standards, and quantum chemical calculations, including 1H and 13C NMR chemical shifts and electronic circular dichroism (ECD) spectra. The three isolated SPA congeners reveal that the characteristic pseudodimeric structure of the SPA family of NPs, likely introduced at a late stage of the SPA biosynthesis, is highly relevant for the observed low nanomolar activity. SPA A exhibits a rapid killing profile, with activities across all intraerythrocytic stages, and potent liver stage efficacy, as well as a low propensity for resistance development. Taken together, these results suggest a mode of action that most likely is distinct from the existing antimalarials, supporting SPA A as a promising antimalarial drug lead for further development.

MeSH

Malaria, Blood, Pharmaceutical Preparations, Liver, Antimalarials