J. T. Munnoch, D. E. Larcombe, R. E. McHugh, J. Bruce, K. Robb, J. T. Croxford, A. B. Kiepas, J. P. Gomez-Escribano, N. A. Crowhurst, A. J. Collis, S. G. Kendrew, B. D. Huckle, B. Wilkinson, I. S. Hunter, P. A. Hoskisson
The domestication of Streptomyces species for antibiotic production involves long-term, iterative mutagenesis and selection, yet the genomic changes driving enhanced production remain unclear. Analysis of five strains from an industrial lineage of Streptomyces clavuligerus using comparative genomics, transcriptomics and phenotypic profiling for dynamic genome architectures with plasmid integration events and chromosomal rearrangements, alongside the accumulation of mutations affecting metabolic pathways and global gene regulation. These changes increased precursor supply and reprogrammed transcription leading to enhanced clavulanic acid production but reduced catabolic flexibility. Complementation experiments confirmed the functional impacts of specific mutations. These findings reveal that artificial selection shapes genome evolution in industrial strains, balancing production gains with metabolic trade-offs. This work will likely inform rational design of Streptomyces strains for improved natural product production in industry while highlighting the constraints imposed by domestication on metabolic versatility. More broadly it shows that many of the evolutionary processes in industrial strain improvement programmes mirror those at play during natural selection.