Genome mining of amylases and amylase inhibitors from Streptomyces

Abstract Most antibiotics are derived from Streptomyces bacteria and produced industrially via fermentations relying on food-grade feedstocks, which has a substantial environmental impact. Efficient utilisation of starch-rich organic wastes such as bread and potato waste as alternative feedstocks remains limited by incomplete knowledge of starch metabolism in Streptomyces. Here, a genus-wide analysis of 295 Streptomyces strains was performed, identifying 645 amylases grouped into pullulanases, α-1,4-amylases, and cyclomaltodextrin-like amylases, alongside biosynthetic gene clusters encoding amylase inhibitors such as acarbose and tendamistat. Structural and sequence analyses revealed that inhibitor resistance arises from subtle modifications in the α-amylase catalytic pocket. This comprehensive analysis of amylases and inhibitors provides a foundation for engineering inhibitor-resistant enzymes tailored to diverse starch substrates, facilitating the development of sustainable, starch-based Streptomyces fermentations. Impact statement Pharmaceutical manufacturing contributes substantially to global carbon emissions, with feedstocks used in natural product fermentations being a major factor. Replacing conventional feedstocks with organic waste streams, such as starch-rich bread or potato waste, could reduce the environmental impact, but two key challenges remain: production strains may lack the enzymes required to efficiently degrade alternative substrates, and nutrient changes may trigger carbon catabolite repression, reducing product yields. While previous studies have linked carbohydrate-active enzymes with biosynthetic gene clusters, no comprehensive analysis has focused specifically on starch degradation in Streptomyces. To fill this gap, a genus-wide analysis of amylases and amylase inhibitors across 295 Streptomyces genomes was carried out. This created an atlas of 645 amylases which may serve as the foundation for the targeted selection of enzymes optimised for catabolising organic waste from various sources, thereby improving the sustainably of industrial natural product production such as antibiotics. Data summary Scripts used along with supplementary files and figures can be accessed through GitHub at https://github.com/ALawaetz/Amylases_and_amylase_inhibitors_in_Streptomycetes. Competing Interest Statement The authors have declared no competing interest.