Abstract
Activation of silent biosynthetic gene clusters in Streptomyces bacteria via overexpression of cluster-specific regulatory genes is a promising strategy for the discovery of novel bioactive secondary metabolites. This approach was used in an attempt to activate a cryptic gene cluster in a marine sponge-derived Streptomyces albus PVA94-07 presumably governing the biosynthesis of peptide-based secondary metabolites. While no new peptide-based metabolites were detected in the recombinant strain, it was shown to produce at least four new analogues of deferoxamine with additional acyl and sugar moieties, for which chemical structures were fully elucidated. Biological activity tests of two of the new deferoxamine analogues revealed weak activity against Escherichia coli. The gene knockout experiment in the gene cluster targeted for activation, as well as overexpression of certain genes from this cluster did not have an effect on the production of these compounds by the strain overexpressing the regulator. It seems plausible that the production of such compounds is a response to stress imposed by the production of an as-yet unidentified metabolite specified by the cryptic cluster.
Highlights
Gram-positive filamentous bacteria belonging to the genus Streptomyces are versatile producers of secondary metabolites, many of which have distinct biological activities
Stimulus.,ititisisnot notsurprising surprisingthat thatthe thebiosynthesis biosynthesisofofsecondary secondarymetabolites metabolitesis tightly regulated on several levels, and most gene clusters contain one or more pathway-specific is tightly regulated on several levels, and most gene clusters contain one or more pathway-specific regulatorsensuring ensuringcoordinated coordinatedexpression expressionofofbiosynthetic biosyntheticgenes genes[3]
The latter feature of secondary metabolite biosynthesis gene clusters has been successfully exploited. The latter feature of secondary metabolite biosynthesis gene clusters has been successfully in order to force the expression of otherwise silent gene clusters to afford the production exploited in order to force the expression of otherwise silent gene clusters to afford of novel compounds
Summary
Gram-positive filamentous bacteria belonging to the genus Streptomyces are versatile producers of secondary metabolites, many of which have distinct biological activities. Streptomyces strain usually harbors 20–50 gene clusters for the biosynthesis of secondary metabolites [2]. Stimulus.,ititisisnot notsurprising surprisingthat thatthe thebiosynthesis biosynthesisofofsecondary secondarymetabolites metabolitesis tightly regulated on several levels, and most gene clusters contain one or more pathway-specific is tightly regulated on several levels, and most gene clusters contain one or more pathway-specific regulatorsensuring ensuringcoordinated coordinatedexpression expressionofofbiosynthetic biosyntheticgenes genes[3] The latter feature of secondary metabolite biosynthesis gene clusters has been successfully in order to force the expression of otherwise silent (or cryptic) gene clusters to afford the production exploited in order to force the expression of otherwise silent (or cryptic) gene clusters to afford of novel compounds. PVA94-07 was targeted for biosynthesis gene cluster in marine sponge-derived Streptomyces albus PVA94-07 was targeted for activation.
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