SUMMARY Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific. Streptomyces coelicolor, the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis in S. coelicolor and other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism9s physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerous Streptomyces genomes.

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Microbial secondary metabolites are low molecular mass products, not essential for growth of the producing cultures, but very important for human health. They include antibiotics, antitumor agents, cholesterol-lowering drugs, and others. They have unusual structures and are usually formed during the late growth phase of the producing microorganisms. Its synthesis can be influenced greatly by manipulating the type and concentration of the nutrients formulating the culture media. Among these nutrients, the effect of the carbon sources has been the subject of continuous studies for both, industry and research groups. Different mechanisms have been described in bacteria and fungi to explain the negative carbon catabolite effects on secondary metabolite production. Their knowledge and manipulation have been useful either for setting fermentation conditions or for strain improvement. During the last years, important advances have been reported on these mechanisms at the biochemical and molecular levels. The aim of the present review is to describe these advances, giving special emphasis to those reported for the genus Streptomyces.

Production of microbial secondary metabolites: Regulation by the carbon source

Antibiotics are low-molecular-mass products of secondary metabolism, nonessential for the growth of producing organisms, but very important for human health. They have unusual structures and are most often formed during the late growth phase of the producing microorganisms. Their production arises from intracellular intermediates, which are condensed into more complex structures through defined biochemical pathways. Their synthesis can be influenced by manipulating the type and concentration of nutrients formulating the culture media. Among them, the effect of the carbon source has been the subject of continuous studies for both industry and research groups. Glucose and other carbohydrates have been reported to interfere with antibiotic synthesis and this effect depends on the rapid utilization of the preferred carbon source. Different mechanisms have been described in bacteria and fungi to explain the negative effects of carbon catabolites on antibiotic production. They show important differences depending on the microbe being considered. Their understanding and manipulation have been useful for both perfecting fermentation conditions to produce anti-infectives and for strain improvement. To improve the production of antibiotics, carbon source repression can be decreased or abolished by mutations resulting in antimetabolite resistance. Enzymes reported as regulated by the carbon source have been used as targets for strain improvement. During the last few years, important advances have been reported elucidating the essential aspects of carbon source regulation on antibiotic production at biochemical and molecular levels. The aim of this review is to describe these advances, giving special emphasis to those reported for the genus Streptomyces.

/pdf/carbon-source-regulation-of-antibiotic-production-228qr7jl56.pdf

Carbon source regulation of antibiotic production

Regulation of antibiotic production in Actinobacteria: new perspectives from the post-genomic era.

Summary Members of the soil-dwelling, sporulating prokaryotic genus Streptomyces are indispensable for the recy- cling of the most abundant polysaccharides on earth (cellulose and chitin), and produce a wide range of antibiotics and industrial enzymes. How do these organisms sense the nutritional state of the environ- ment, and what controls the signal for the switch to antibiotic production and morphological develop- ment? Here we show that high extracellular concen- trations of N-acetylglucosamine, the monomer of chitin, prevent Streptomyces coelicolor progressing beyond the vegetative state, and that this effect is absent in a mutant defective of N-acetylglucosamine transport. We provide evidence that the signal is transmitted through the GntR-family regulator DasR, which controls the N-acetylglucosamine regulon, including the pts genes ptsH, ptsI and crr needed for uptake of N-acetylglucosamine. Deletion of dasR or the pts genes resulted in a bald phenotype. Binding of DasR to its target genes is abolished by glucosamine 6-phosphate, a central molecule in N-acetylglucosamine metabolism. Extracellular com- plementation experiments with many bld mutants showed that the dasR mutant is arrested at an early stage of the developmental programme, and does not fit in the previously described bld signalling cascade. Thus, for the first time we are able to directly link carbon (and nitrogen) metabolism to development, highlighting a novel type of metabolic regulator, which senses the nutritional state of the habitat, maintaining vegetative growth until changing circum- stances trigger the switch to sporulation. Our work, and the model it suggests, provide new leads towards understanding how microorganisms time develop- mental commitment.

/pdf/the-sugar-phosphotransferase-system-of-streptomyces-n9c7phtz8c.pdf

The sugar phosphotransferase system of Streptomyces coelicolor is regulated by the GntR-family regulator DasR and links N-acetylglucosamine metabolism to the control of development.

We have demonstrated that the bldB gene of Streptomyces coelicolor is required for the formation of aerial hyphae and the synthesis of antibiotics. We also found that BldB forms a higher-order complex (most likely a dimer) and that amino acid residues 20 to 78 are important for this interaction. This region is conserved in the BldB family, suggesting that dimer formation may be a common feature of these proteins.

Structural and Genetic Analysis of the BldB Protein of Streptomyces coelicolor

The bldB gene of Streptomyces coelicolor encodes the best-characterized member of a family of small proteins that have low isoelectric points but that lack any previously characterized sequence motifs. BldB is dimeric and is required for the efficient production of antibiotics and spore-forming cells, called aerial hyphae, by growing colonies. The mechanism of action of BldB and its relatives is unknown. Here, we have explored amino acids in BldB that either are highly conserved or have been implicated in function genetically. We show that five amino acids are important for its function at physiological expression levels. Mutations in three of these amino acids gave rise to proteins that were either monomeric or unstable in vivo, while two others are not. We find that overexpression of bldB in S. coelicolor blocks sporulation prior to sporulation-specific septation but permits the formation of aerial hyphae. Vegetative septation was apparently normal in both the bldB null mutant and the bldB overexpression strain. To our surprise, overexpression of the dimerization-competent but functionally defective alleles caused a dramatic acceleration of sporulation. Our results suggest that BldB makes at least one important contact with another subcellular constituent and that a loss or alteration of this interaction impairs the phenotypic properties of the organism.

Critical Residues and Novel Effects of Overexpression of the Streptomyces coelicolor Developmental Protein BldB: Evidence for a Critical Interacting Partner

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Structural and Genetic Analysis of the BldB Protein of Streptomyces coelicolor

Critical Residues and Novel Effects of Overexpression of the Streptomyces coelicolor Developmental Protein BldB: Evidence for a Critical Interacting Partner