Secondary Nucleotide Messenger C-Di-GMP Exerts a Global Control on Natural Product Biosynthesis in Streptomycetes
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Authors
Makitrynskyy, Roman
Tsypik, Olga
Nuzzo, Desiree
Paululat, Thomas
Zechel, David
Bechthold, Andreas
Date
2020-01-16
Type
journal article
Language
en
Keyword
Synthetic biology , Synthetic bioengineering
Alternative Title
Abstract
Cyclic dimeric 3′-5′ guanosine monophosphate, c-di-GMP, is a ubiquitous second messenger controlling diverse cellular processes in bacteria. In streptomycetes, c-di-GMP plays a crucial role in a complex morphological differentiation by modulating an activity of the pleiotropic regulator BldD. Here we report that c-di-GMP plays a key role in regulating secondary metabolite production in streptomycetes by altering the expression levels of bldD. Deletion of cdgB encoding a diguanylate cyclase in Streptomycesghanaensis reduced c-di-GMP levels and the production of the peptidoglycan glycosyltransferase inhibitor moenomycin A. In contrast to the cdgB mutant, inactivation of rmdB, encoding a phosphodiesterase for the c-di-GMP hydrolysis, positively correlated with the c-di-GMP and moenomycin A accumulation. Deletion of bldD adversely affected the synthesis of secondary metabolites in S. ghanaensis, including the production of moenomycin A. The bldD-deficient phenotype is partly mediated by an increase in expression of the pleiotropic regulatory gene wblA. Genetic and biochemical analyses demonstrate that a complex of c-di-GMP and BldD effectively represses transcription of wblA, thus preventing sporogenesis and sustaining antibiotic synthesis. These results show that manipulation of the expression of genes controlling c-di-GMP pool has the potential to improve antibiotic production as well as activate the expression of silent gene clusters.
Description
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Citation
Roman Makitrynskyy, Olga Tsypik, Desirèe Nuzzo, Thomas Paululat, David L Zechel, Andreas Bechthold, Secondary nucleotide messenger c-di-GMP exerts a global control on natural product biosynthesis in streptomycetes, Nucleic Acids Research, Volume 48, Issue 3, 20 February 2020, Pages 1583–1598, https://doi.org/10.1093/nar/gkz1220
Publisher
Oxford Academic