Multi-omics Study of Planobispora rosea, Producer of the Thiopeptide Antibiotic GE2270A

Planobispora rosea is the natural producer of the potent thiopeptide antibiotic GE2270A. Here, we present the results of a metabolomics and transcriptomics analysis of P. rosea during production of GE2270A. The data generated provides useful insights into the biology of this genetically intractable bacterium. We characterize the details of the shutdown of protein biosynthesis and the respiratory chain associated with the end of the exponential growth phase. We also provide the first description of the phosphate regulon in P. rosea. Based on the transcriptomics data, we show that both phosphate and iron are limiting P. rosea growth in our experimental conditions. Additionally, we identified and validated a new biosynthetic gene cluster associated with the production of the siderophores benarthin and dibenarthin in P. rosea. Together, the metabolomics and transcriptomics data are used to inform and refine the very first genome-scale metabolic model for P. rosea, which will be a valuable framework for the interpretation of future studies of the biology of this interesting but poorly characterized species. IMPORTANCE Planobispora rosea is a genetically intractable bacterium used for the production of GE2270A on an industrial scale. GE2270A is a potent thiopeptide antibiotic currently used as a precursor for the synthesis of two compounds under clinical studies for the treatment of Clostridium difficile infection and acne. Here, we present the very first systematic multi-omics investigation of this important bacterium, which provides a much-needed detailed picture of the dynamics of metabolism of P. rosea while producing GE2270A

Multi-omics Study of Planobispora rosea, Producer of the Thiopeptide Antibiotic GE2270A

[EN] Planobispora rosea is the natural producer of the potent thiopeptide antibiotic GE2270A. Here, we present the results of a metabolomics and transcriptomics analysis of P. rosea during production of GE2270A. The data generated provides useful insights into the biology of this genetically intractable bacterium. We characterize the details of the shutdown of protein biosynthesis and the respiratory chain associated with the end of the exponential growth phase. We also provide the first description of the phosphate regulon in P. rosea. Based on the transcriptomics data, we show that both phosphate and iron are limiting P. rosea growth in our experimental conditions. Additionally, we identified and validated a new biosynthetic gene cluster associated with the production of the siderophores benarthin and dibenarthin in P. rosea. Together, the metabolomics and transcriptomics data are used to inform and refine the very first genome-scale metabolic model for P. rosea, which will be a valuable framework for the interpretation of future studies of the biology of this interesting but poorly characterized speciesSIF.D.C., M.I., M.P.-B., K.S., R.P.-R., M.S., S.J.M., I.S.G., A.T., G.H.T., O.G., A.R.-G., S.D., R.B., and E.T. were funded by the European Union’s Horizon 2020 Research and Innovation Program under grant agreement 720793 “TOPCAPI: Thoroughly Optimised Production Chassis for Advanced Pharmaceutical Ingredients.” S.J.M., I.S.G., and G.H.T. were also supported from BBSRC IB Catalyst program, DETOX (BB/N01040X/1). We thank the Manchester Synthetic Biology Research Centre SYNBIOCHEM team, especially Katherine Hollywood, for their support and use of the QExactive for the untargeted metabolomics analysis. We thank all the TOPCAPI consortium partners for their support. F.D.C. performed the data processing of the metabolomics data, performed the statistical analysis of the transcriptomics and metabolomics data, and wrote the first draft of the manuscript. M.I. and M.S. prepared the samples for the transcriptomics and metabolomics analysis and performed the supplementation experiment. M.P.-B. and K.S. performed the metabolomics analysis and the data processing. R.P.-R. performed the RNA extraction and quality control. S.M. and I.G. processed and analyzed data included in MORF. F.D.C. and A.T. built the genome-scale metabolic model. F.D.C., A.T., and A.R.-G. performed RNAseq analyses. G.H.T., O.G., A.R.-G., S.D., R.B., and E.T. conceived the experiments, analyzed the data, and coordinated the activities. F.D.C., M.P.-B., K.S., G.H.T., A.R.-G., S.D., R.B., and E.T. contributed to writing the manuscript. All the authors edited and approved the final version