Abstract
Streptomycetes are filamentous bacteria famous for their ability to produce a vast majority of clinically important secondary metabolites. Both complex morphogenesis and onset of antibiotic biosynthesis are tightly linked in streptomycetes and require series of specific signals for initiation. Cyclic dimeric 3′–5′ guanosine monophosphate, c-di-GMP, one of the well-known bacterial second messengers, has been recently shown to govern morphogenesis and natural product synthesis in Streptomyces by altering the activity of the pleiotropic regulator BldD. Here we report a role of the heme-binding diguanylate cyclase SSFG_02181 from Streptomyces ghanaensis in the regulation of the peptidoglycan glycosyltransferase inhibitor moenomycin A biosynthesis. Deletion of ssfg_02181 reduced the moenomycin A accumulation and led to a precocious sporulation, while the overexpression of the gene blocked sporogenesis and remarkably improved antibiotic titer. We also demonstrate that BldD negatively controls the expression of ssfg_02181, which stems from direct binding of BldD to the ssfg_02181 promoter. Notably, the heterologous expression of ssfg_02181 in model Streptomyces spp. arrested morphological progression at aerial mycelium level and strongly altered the production of secondary metabolites. Altogether, our work underscores the significance of c-di-GMP-mediated signaling in natural product biosynthesis and pointed to extensively applicable approach to increase antibiotic production levels in streptomycetes.
Highlights
Cyclic dimeric (3′ → 5′) GMP (c-di-GMP) was initially reported by Ross et al.[1] in 1987 as an allosteric activator of a bacterial cellulose synthase
We show that the expression of ssfg_02181 remarkably influences antibiotic biosynthesis and morphological differentiation in S. ghanaensis
In the past few years, c-di-GMP has emerged as a crucial molecule involved in streptomycetes development, controlling both morphogenesis and secondary metabolite production[9,10,11,12,14,15]
Summary
Cyclic dimeric (3′ → 5′) GMP (c-di-GMP) was initially reported by Ross et al.[1] in 1987 as an allosteric activator of a bacterial cellulose synthase. PAS (Per-Arnt-Sim) and GAF (mammalian cGMP-regulated PDEs, Anabaena adenylyl cyclases and Escherichia coli transcription activator FhlA) domains are the most spread among c-di-GMP metabolizing enzymes[2] Due to their high plasticity, PAS domains are able to bind a large variety of ligands, such as heme, divalent cations and small molecules. Homodimeric BldD binds to its target promoter sequences, controlling the transcription of developmental-related genes during the vegetative growth[14] It was demonstrated in S. coelicolor that cdgA and cdgB are direct targets of B ldD9,13, revealing another layer of regulation for c-di-GMP metabolizing enzymes. We focused our attention on ssfg_02181, a gene encoding a putative DGC enzyme in Streptomyces ghanaensis ATCC14672 This strain is famous for the production of a mixture of phosphoglycolipids known as moenomycins[20]. Heterologous expression of ssfg_02181 in S. coelicolor and Streptomyces albus displayed a phenotype similar to that gained in S. ghanaensis, suggesting that c-di-GMP may play a conservative role among Streptomyces spp
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