Mining Symbionts of a Spider-Transmitted Fungus Illuminates Uncharted Biosynthetic Pathways to Cytotoxic Benzolactones.
biosynthesis
drug discovery
genome mining
natural products
symbiosis
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
11 05 2020
11 05 2020
Historique:
received:
13
12
2019
pubmed:
11
2
2020
medline:
16
3
2021
entrez:
11
2
2020
Statut:
ppublish
Résumé
A spider-transmitted fungus (Rhizopus microsporus) that was isolated from necrotic human tissue was found to harbor endofungal bacteria (Burkholderia sp.). Metabolic profiling of the symbionts revealed a complex of cytotoxic agents (necroximes). Their structures were characterized as oxime-substituted benzolactone enamides with a peptidic side chain. The potently cytotoxic necroximes are also formed in symbiosis with the fungal host and could have contributed to the necrosis. Genome sequencing and computational analyses revealed a novel modular PKS/NRPS assembly line equipped with several non-canonical domains. Based on gene-deletion mutants, we propose a biosynthetic model for bacterial benzolactones. We identified specific traits that serve as genetic handles to find related salicylate macrolide pathways (lobatamide, oximidine, apicularen) in various other bacterial genera. Knowledge of the biosynthetic pathway enables biosynthetic engineering and genome-mining approaches.
Identifiants
pubmed: 32040253
doi: 10.1002/anie.201916007
pmc: PMC7318616
doi:
Substances chimiques
Lactones
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7766-7771Informations de copyright
© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Références
Angew Chem Int Ed Engl. 2018 Oct 26;57(44):14519-14523
pubmed: 30025185
Curr Biol. 2007 May 1;17(9):773-7
pubmed: 17412585
J Antibiot (Tokyo). 2003 Nov;56(11):899-904
pubmed: 14763554
Nature. 2005 Oct 6;437(7060):884-8
pubmed: 16208371
Int J Syst Evol Microbiol. 2007 Nov;57(Pt 11):2583-2590
pubmed: 17978222
J Pharmacol Exp Ther. 2001 Apr;297(1):114-20
pubmed: 11259534
Plant Dis. 2000 Nov;84(11):1212-1216
pubmed: 30832169
J Antibiot (Tokyo). 2006 Oct;59(10):664-8
pubmed: 17191683
Nature. 2009 Oct 22;461(7267):1139-43
pubmed: 19847268
Appl Environ Microbiol. 2008 Aug;74(16):5121-9
pubmed: 18567690
Nucleic Acids Res. 2019 Jul 2;47(W1):W81-W87
pubmed: 31032519
Clin Microbiol Rev. 2000 Apr;13(2):236-301
pubmed: 10756000
Sci Rep. 2015 May 21;5:10463
pubmed: 25995122
Nat Biotechnol. 2008 Feb;26(2):225-33
pubmed: 18223641
Angew Chem Int Ed Engl. 2012 Sep 17;51(38):9615-8
pubmed: 22915379
Angew Chem Int Ed Engl. 2018 Sep 3;57(36):11644-11648
pubmed: 29898240
Cancer Treat Rev. 2009 Dec;35(8):707-13
pubmed: 19758758
Med J Aust. 1988 Mar 7;148(5):258-9
pubmed: 3343958
J Antibiot (Tokyo). 1998 Jan;51(1):14-20
pubmed: 9531982
J Org Chem. 1997 Nov 14;62(23):8188-8192
pubmed: 11671930
J Am Chem Soc. 2006 Sep 6;128(35):11529-36
pubmed: 16939276
ACS Chem Biol. 2014 Oct 17;9(10):2374-81
pubmed: 25089587
Angew Chem Int Ed Engl. 2019 Sep 9;58(37):13024-13029
pubmed: 31276269
ISME J. 2011 Feb;5(2):252-61
pubmed: 20720578
J Antibiot (Tokyo). 1998 Dec;51(12):1075-80
pubmed: 10048565
Angew Chem Int Ed Engl. 2020 May 11;59(20):7761-7765
pubmed: 32040255
J Org Chem. 1999 Jan 8;64(1):153-155
pubmed: 11674097
Appl Environ Microbiol. 2009 May;75(9):2982-6
pubmed: 19286793
Mol Microbiol. 2005 Nov;58(4):1102-13
pubmed: 16262793
Angew Chem Int Ed Engl. 2010 Feb 15;49(8):1460-4
pubmed: 20033973
Angew Chem Int Ed Engl. 2020 May 11;59(20):7766-7771
pubmed: 32040253
Chem Rev. 2013 Mar 13;113(3):2182-204
pubmed: 23205964
Methods Enzymol. 2009;458:181-217
pubmed: 19374984
Science. 2008 Apr 11;320(5873):243-6
pubmed: 18403714
Angew Chem Int Ed Engl. 2010 Feb 15;49(8):1465-7
pubmed: 20087918