Research Article: Uncovering production of specialized metabolites by Streptomyces argillaceus: Activation of cryptic biosynthesis gene clusters using nutritional and genetic approaches

Date Published: May 24, 2018

Publisher: Public Library of Science

Author(s): Adriana Becerril, Susana Álvarez, Alfredo F. Braña, Sergio Rico, Margarita Díaz, Ramón I. Santamaría, José A. Salas, Carmen Méndez, Marie-Joelle Virolle.


Sequencing of Streptomyces genomes has revealed they harbor a high number of biosynthesis gene cluster (BGC), which uncovered their enormous potentiality to encode specialized metabolites. However, these metabolites are not usually produced under standard laboratory conditions. In this manuscript we report the activation of BGCs for antimycins, carotenoids, germicidins and desferrioxamine compounds in Streptomyces argillaceus, and the identification of the encoded compounds. This was achieved by following different strategies, including changing the growth conditions, heterologous expression of the cluster and inactivating the adpAa or overexpressing the abrC3 global regulatory genes. In addition, three new carotenoid compounds have been identified.

Partial Text

Streptomyces are Gram-positive bacteria with high GC content that show a differentiation cycle. They are known for being a prolific source of secondary metabolites (also referred here as specialized metabolites) [1], many of which show some kind of bioactivity [2]; for example, about 39% of bioactive compounds produced by microorganisms have a Streptomyces origin [3]. Traditionally, any Streptomyces strain was known to produce only one or a few specialized metabolites. However, since the first Streptomyces genome was sequenced it was brought to light that they harbored a higher number of biosynthesis gene clusters (BGC) than expected, which untapped their enormous potential to synthesize bioactive compounds [4]. During the last years, due to the development of next-generation sequencing technologies and bioinformatics tools such as AntiSMASH [5] and MIBiG [6] to identify candidate BGCs, a huge number of Streptomyces genome sequences has been made public, confirming their potential for synthesizing specialized metabolites [4,7]. Curiously, most of these metabolites are not usually identified under standard laboratory growth conditions even those compounds encoded by BGCs frequently found in Streptomyces genomes, which indicate that many of these BGCs are poorly or not expressed under those conditions. Therefore, several strategies have been developed to activate these silent BGCs and to identify the encoded compounds, which involves either genetic and/or culture conditions interventions [7–9].




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