Crp Is a Global Regulator of Antibiotic Production in <i>Streptomyces</i>
Bibliographic record
Abstract
Cyclic AMP receptor protein (Crp) is a transcription regulator controlling diverse cellular processes in many bacteria. In Streptomyces coelicolor, it is well established that Crp plays a critical role in spore germination and colony development. Here, we demonstrate that Crp is a key regulator of secondary metabolism and antibiotic production in S. coelicolor and show that it may additionally coordinate precursor flux from primary to secondary metabolism. We found that crp deletion adversely affected the synthesis of three well-characterized antibiotics in S. coelicolor: actinorhodin (Act), undecylprodigiosin (Red), and calcium-dependent antibiotic (CDA). Using chromatin immunoprecipitation-microarray (ChIP-chip) assays, we determined that eight (out of 22) secondary metabolic clusters encoded by S. coelicolor contained Crp-associated sites. We followed the effect of Crp induction using transcription profiling analyses and found secondary metabolic genes to be significantly affected: included in this Crp-dependent group were genes from six of the clusters identified in the ChIP-chip experiments. Overexpressing Crp in a panel of Streptomyces species led to enhanced antibiotic synthesis and new metabolite production, suggesting that Crp control over secondary metabolism is broadly conserved in the streptomycetes and that Crp overexpression could serve as a powerful tool for unlocking the chemical potential of these organisms. IMPORTANCE Streptomyces produces a remarkably diverse array of secondary metabolites, including many antibiotics. In recent years, genome sequencing has revealed that these products represent only a small proportion of the total secondary metabolite potential of Streptomyces. There is, therefore, considerable interest in discovering ways to stimulate the production of new metabolites. Here, we show that Crp (the classical regulator of carbon catabolite repression in Escherichia coli) is a master regulator of secondary metabolism in Streptomyces. It binds to eight of 22 secondary metabolic gene clusters in the Streptomyces coelicolor genome and directly affects the expression of six of these. Deletion of crp in S. coelicolor leads to dramatic reductions in antibiotic levels, while Crp overexpression enhances antibiotic production. We find that the antibiotic-stimulatory capacity of Crp extends to other streptomycetes, where its overexpression activates the production of "cryptic" metabolites that are not otherwise seen in the corresponding wild-type strain.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".