Divalent Transition‐Metal‐Ion Stress Induces Prodigiosin Biosynthesis in Streptomyces coelicolor M145: Formation of Coeligiosins

Abstract

The bacterium Streptomyces coelicolor M145 reacts to transition-metal-ion stress with myriad growth responses, leading to different phenotypes. In particular, in the presence of Co 2 + ions (0.7 mm) S. coelicolor consistently produced a red phenotype. This phenotype, when compared to the wild type, differed strongly in its production of volatile compounds as well as high molecular weight secondary metabolites. LC-MS analysis revealed that in the red phenotype the production of the prodigiosins, undecylprodigiosin and streptorubin B, was strongly induced and, in addition, several intense signals appeared in the LC-MS chromatogram. Using LC-MS/MS and NMR spectroscopy, two new prodigiosin derivatives were identified, that is, coeligiosin A and B, which contained an additional undecylpyrrolyl side chain attached to the central carbon of the tripyrrole ring system of undecylprodigiosin or streptorubin B. This example demonstrates that environmental factors such as heavy metal ion stress can not only induce the production of otherwise not observed metabolites from so called sleeping genes but alter the products from well-studied biosynthetic pathways.In their natural environment, microorganisms such as Actinomyces have to cope with changing and sometimes adverse conditions. Microorganisms not only rapidly adapt under evolutionary pressure [1] but their genomes contain a great repertoire of secondary metabolite genes [2] that can ensure their survival.Actinomyces are most well-known for their secondary metabolites, such as polyketides or non-ribosomal peptides, many of which turned out to be of invaluable pharmaceutical use, for example, as antibiotics. [3] The variation of fermentation conditions has been intensively used in order to optimize the production of secondary metabolites in biotechnological processes.[4] Bode et al. systematically varied growth conditions in order to induce the formation of diverse secondary metabolites in a selected Streptomyces strain and termed their approach OSMAC (one strain many compounds).[5] With the genome sequencing of many Actinomyces such as the model Streptomycete Streptomyces coelicolor A3(2), [6] it became evident that these antibiotic producers comprise a lot more secondary metabolite gene clusters than secondary metabolites that have been identified from them. [2,7] Clearly, the maintenance of secondary metabolite gene clusters and their formation is costly for the producing strains.[8] In contrast to laboratory cultivation under optimized growth conditions, in their natural environment microorganisms have to cope with biotic and abiotic stress factors, for example, competition for space and nutrients. In such scenarios secondary metabolites are likely specifically and flexibly produced to ensure survival under varying and challenging growth conditions. In nature, therefore, microorganisms most likely produce secondary metabolites from "silent gene clusters" to react to their environment. Biotic and abiotic factors influence the microorganisms, leading to morpholo...

Streptomyces sp. MUM273b: A mangrove‐derived potential source for antioxidant and UVB radiation protectants

“…In line with several previous studies, these groups of chemicals were also reported in the bacterial fermentation broth or extracts derived from Actinomycetes and Streptomyces sp. For instance, dimethyltrisulfide ( 1 ) (Groenhagen, Maczka, Dickschat, & Schulz, ), trimethylpyrazine ( 2 ) (Citron, Barra, Wink, & Dickschat, ), 2‐acetylpyrrole ( 3 ) (Morgenstern, Paetz, Behrend, & Spiteller, ), pyrazine,2,5‐dimethyl‐3‐(3‐methylbutyl) ( 4 ) (Citron et al, ), phenol,2,4‐bis(1,1‐dimethylethyl)‐ ( 8 ) (Kumar, Duraipandiyan, & Ignacimuthu, ), benzoic acid,4‐ethoxy‐,ethyl ester ( 9 ) (Sharma, Goel, Dureja, & Uniyal, ), (3R,8aS)‐3‐methyl‐1,2,3,4,6,7,8,8a‐octahydropyrrolo[1,2a]pyrazine‐1,4‐dione ( 13 ) (Tan et al, ), pyrrolo[1,2a]pyrazine‐1,4‐dione, hexahydro ( 14 ) (Ser, Palanisamy, et al, ), 1,4‐diaza‐2,5‐dioxo‐3‐isobutyl bicyclo[4.3.0]nonane ( 15 ) (Ser, Ab Mutalib, et al, ), 9H‐Pyrido[3,4‐b]indole ( 16 ) (Tan, Ser, et al, ), 2,5‐piperazinedione, 3‐(1‐methylethyl)‐6‐(phenylmethyl)‐ ( 17 ) (Alshaibani et al, ), 3‐benzyl‐1,4‐diaza‐2,5‐dioxobicyclo[4.3.0]nonane ( 18 ) (Jog, Pandya, Nareshkumar, & Rajkumar, ; Sharma, Kalita, & Thakur, ) and phenol,2,2′‐methylenebis[6‐(1,1‐dimethylethyl)‐4‐methyl‐ ( 19 ) (Tan, Ser, et al, ).…”

Plant growth promotion by streptomycetes: ecophysiology, mechanisms and applications

“…This production of secondary metabolites is attributed to the development of aerial hyphae as a result of nutrient limitation [47]. The biological activity of these compounds involves inhibitory or microbiocide activity against microorganisms (i.e., antibiotics), toxicity against metazoans, microbial hormonelike activity, and metal transport [48][49][50]. It has been well demonstrated that the secondary metabolites produced by streptomycetes increases adaptation to biological, physical, and chemical stresses; thus, they are recognized as 'stress metabolites' [36].…”

Production of Prodiginines Is Part of a Programmed Cell Death Process in Streptomyces coelicolor

“…Time-space monitoring of redD expression, the activator of PdGs red biosynthetic genes, is also confined to aging, lysed filaments ( Sun et al, 1999 ). Moreover, prodigiosin-like pigments are induced by stressing culture conditions like excess of metal ions and pH shock ( Mo et al, 2013 ; Morgenstern et al, 2015 ), co-cultivation with competing microorganisms ( Luti and Mavituna, 2011b ; Schäberle et al, 2014 ), and feeding the medium with dead bacterial cells ( Luti and Mavituna, 2011a ). Finally, all other DNA-damaging agents have been shown to be toxic for the producing actinobacterial species ( Tenconi and Rigali, 2018 ).…”