Abstract
Streptomyces antibiotic regulatory protein (SARP) family regulators are well-known activators of antibiotic biosynthesis in streptomycetes. The respective genes occur in various types of antibiotic gene clusters encoding, e.g., for polyketides, ribosomally and non-ribosomally synthesized peptides, or β-lactam antibiotics. We found that overexpression of the SARP-type regulator gene papR2 from Streptomyces pristinaespiralis in Streptomyces lividans leads to the activation of the silent undecylprodigiosin (Red) gene cluster. The activation happens upon the inducing function of PapR2, which takes over the regulatory role of RedD, the latter of which is the intrinsic SARP regulator of Red biosynthesis in S. lividans. Due to the broad abundance of SARP genes in different antibiotic gene clusters of various actinomycetes and the uniform activating principle of the encoded regulators, we suggest that this type of regulator is especially well suited to be used as an initiator of antibiotic biosynthesis in actinomycetes. Here, we report on a SARP-guided strategy to activate antibiotic gene clusters. As a proof of principle, we present the PapR2-driven activation of the amicetin/plicacetin gene cluster in the novel Indonesian strain isolate Streptomyces sp. SHP22-7.
Highlights
In 2018, the WHO warned that the dramatic increase of antibiotic resistances coupled with the scarcity of new antibiotics will lead to a global health crisis in the 21st century (World Health Organization, 2015)
We demonstrate that the SARPtype regulator PapR2 activates the silent undecylprodigiosin (Red) gene cluster in Streptomyces lividans
Red biosynthesis has mainly been studied in S. coelicolor; since S. coelicolor and S. lividans are very closely related species, knowledge on Red biosynthesis and regulation can be transferred to S. lividans.To investigate, whether the red color of the SLpapR2-OE cultures originates from the formation of the Red metabolite, we performed spectrophotometrical analysis
Summary
In 2018, the WHO warned that the dramatic increase of antibiotic resistances coupled with the scarcity of new antibiotics will lead to a global health crisis in the 21st century (World Health Organization, 2015). There are several attempts to activate silent gene cluster expression in order to find new antibiotics Most of these activation efforts are either (a) completely unspecific in terms of the BGC(s) to be activated [e.g., by adding general elicitors to the cell culture, co-cultivation approaches, or strain-cultivations following the “one strain-many compounds” (OSMAC) strategy] or (b) they are absolutely specific for the BGC of interest (e.g., heterologous expression of the BGC, introduction of an artificial promoter in front of the BGC, or manipulation of a cluster-situated regulator) as reviewed in Ochi and Hosaka (2013) and Zhu et al (2014). SHP22-7 (SHP22-7), which yielded an increased production of the nucleoside antibiotic plicacetin
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