Impact of Nitrogen-Containing Compounds on Secondary Metabolism in Streptomyces spp.—A Source of Metabolic Engineering Strategies

Abstract

Actinobacteria from the genus Streptomyces feature complex primary and secondary metabolism, developmental cycle, and ability to produce a variety of natural products. These soil bacteria are major producers of antibiotics and other bioactive compounds and have been extensively investigated due to the medical and industrial relevance of Streptomyces-derived secondary metabolites. However, the genetic toolbox for Streptomyces engineering as well as yield optimization strategies for the production of relevant metabolites are limited. On the one hand, the genetic potential of these organisms has not been fully utilized due to many “silent” or poorly expressed biosynthetic gene clusters, whose activation depends on environmental stimuli and nutrient availability. On the other hand, these GC-rich Gram-positive bacteria are difficult to manipulate, and traditional genetic manipulation strategies are time-consuming and have low efficiency. Recent studies of Streptomyces metabolism and genomes provided new insights into possibilities to overcome these challenges. In this review, advances and approaches for Streptomyces manipulations and secondary metabolite production optimization are discussed. Special focus is given to understanding the interplay between primary and secondary metabolism in Streptomyces and the supply of nitrogen-containing compounds into secondary metabolism. Existing strategies to manipulate cellular metabolism in Streptomyces are reviewed.

Whole Genome Analysis of Streptomyces spp. Strains Isolated from the Rhizosphere of Vitis vinifera L. Reveals Their Role in Nitrogen and Phosphorus Metabolism

“…Regarding the assimilation of ammonia, it plays a crucial role in the overall nitrogen metabolism of organisms. The process is regulated by the glutamine synthetase complex, specifically through the involvement of glnA and glnD, which control nitrogen metabolism transcriptionally in response to nitrogen concentration [55,57,58,64]. On the other hand, the utilization of allantoin is of significant importance in various organisms as it serves as a nitrogen and carbon source.…”

An overview of the two-component system GarR/GarS role on antibiotic production in Streptomyces coelicolor

“…Under laboratory conditions, Streptomyces coelicolor has been adopted as one of the models for regulatory studies on antibiotic biosynthesis because of its amenability to genetic analysis and rapid response detection due to its ability to produce two pigmented secondary metabolites known as actinorhodin (ACT) (Wright and Hopwood 1976 ) and undecylprodigiosin (RED) (Rudd and Hopwood 1980 ). The production of these and other secondary metabolites is influenced by environmental nutrients like carbon, nitrogen, and phosphate when available in the culture media (Romero-Rodríguez et al 2016a ; Krysenko 2023 ; Barreiro and Martínez-Castro 2019 ). The effect of the carbon source on the synthesis of secondary metabolites has been extensively studied in Streptomyces (Romero-Rodríguez et al 2016a ; Guzmán et al 2005 ; Gubbens et al 2012 ; Magdalena et al 2012 ; Tierrafría et al 2016 ), which is regulated by a mechanism known as carbon catabolite repression (CCR) (Ruiz-Villafán et al 2021 ).…”

Genomic Insights and Synthetic Biology Applications of Marine Actinomycete Streptomyces griseoincarnatus HNS054

“…Actinomycete chassis cells undergo diverse genetic enhancements, involving genome simplification [ 11 ], removal of native secondary metabolite BGCs [ 12 ], insertion of site-specific recombination (SSR) system attB loci to integrate multiple foreign BGCs [ 13 ], and removal of negative regulators of BGC expression [ 14 , 15 ]. These modifications aim to enhance the heterologous expression of foreign BGCs [ 16 ]. Consequently, potential hosts earmarked as chassis should be compatible with genetic engineering tools.…”