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The natural product argyrin B inhibits bacteria and eukaryotic cell growth by inhibition of elongation factor G1.

Nyfeler, Beat, Hoepfner, Dominic, Palestrant, Deborah, Kirby, Christina, Whitehead, Lewis, Yu, Robert, Deng, Gejing, Caughlan, Ruth, Woods, Angela, Jones, Adriana, Barnes, Whitney, Walker, John, Gaulis, Swann, Hauy, Ervan, Brachmann, Saskia, Krastel, Philipp, Studer, Christian, Riedl, Ralph, Estoppey, David, Aust, Thomas, Movva, Rao, Wang, Zuncai, Salcius, Michael, Michaud, Gregory, Mcallister, Gregory, Murphy, Leon, Tallarico, John, Wilson, Christopher, Myer, Vic and Dean, Charles (2012) The natural product argyrin B inhibits bacteria and eukaryotic cell growth by inhibition of elongation factor G1. PLoS ONE, 7 (9). pp. 1-12. ISSN 1932-6203

Abstract

Argyrins are cyclic octapeptides that have antibacterial, immunosuppressive and antitumor activity. Using bacterial mutant selection and whole genome sequencing, we identified elongation factor G (EF-G) as the cellular target of argyrin B. Purified EF-G bound argyrin tightly, and the co-crystal structure of EF-G in complex with argyrin B revealed a novel binding pocket that was clearly delineated by the locations of resistance determining amino acid subtitutions. In eukaryotic cells, argyrin B was found to inhibit mitochondrial elongation factor G1 (a close homologue of EF-G), thereby blocking mitochondrial translation, depleting electron transport components, and inhibiting the growth of rapidly dividing tumor cells. This study identifies argyrin B as an antibacterial and cytotoxic agent that inhibits EF-G, a target which is evolutionarily conserved from bacteria to yeast to mammalian cells.

Item Type: Article
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Keywords: argyrin natural product antibacterial elongation factor G cytotoxicity mitochondria
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6511

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