title: Discovery of potent broad spectrum antivirals derived from marine actinobacteria.
abstract: Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the continued development of broadly active antiviral compounds.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Avi
authors.initials: A
authors.lastname: Raveh
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Phillip C
authors.initials: PC
authors.lastname: Delekta
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Dobry
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Weiping
authors.initials: W
authors.lastname: Peng
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Schultz
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Pennelope K
authors.initials: PK
authors.lastname: Blakely
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Tai
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 Neurology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: David N
authors.initials: DN
authors.lastname: Irani
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America ; Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan, United States of America ; Department of Chemistry and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherman
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America ; Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Miller
mesh_terms: D039903:Actinobacteria / Q000737:chemistry*; D000818:Animals; D000968:Antimycin A / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology / Q000821:virology; D005591:Chemical Fractionation; D004579:Electron Transport / Q000187:drug effects; D004668:Encephalitis Viruses / Q000187:drug effects; D004671:Encephalitis, Arbovirus / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D019015:Geologic Sediments / Q000382:microbiology*; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D012015:Reference Standards; D015203:Reproducibility of Results; D013302:Streptomyces / Q000737:chemistry; D016019:Survival Analysis; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001688:Biological Products; D012367:RNA, Viral; D000968:Antimycin A