20.500.12556/DiRROS-20181 Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus Most biosynthetic gene clusters (BGC) encoding the synthesis of important microbial secondary metabolites, such as antibiotics, are either silent or poorly expressed; therefore, to ensure a strong pipeline of novel antibiotics, there is a need to develop rapid and efficient strain development approaches. This study uses comparative genome analysis to instruct rational strain improvement, using Streptomyces rimosus, the producer of the important antibiotic oxytetracycline (OTC) as a model system. Sequencing of the genomes of two industrial strains M4018 and R6-500, developed independently from a common ancestor, identified large DNA rearrangements located at the chromosome end. We evaluated the effect of these genome deletions on the parental S. rimosus Type Strain (ATCC 10970) genome where introduction of a 145 kb deletion close to the OTC BGC in the Type Strain resulted in massive OTC overproduction, achieving titers that were equivalent to M4018 and R6-500. Transcriptome data supported the hypothesis that the reason for such an increase in OTC biosynthesis was due to enhanced transcription of the OTC BGC and not due to enhanced substrate supply. We also observed changes in the expression of other cryptic BGCs; some metabolites, undetectable in ATCC 10970, were now produced at high titers. This study demonstrated for the first time that the main force behind BGC overexpression is genome rearrangement. This new approach demonstrates great potential to activate cryptic gene clusters of yet unexplored natural products of medical and industrial value. genome reduction antibiotic biosynthesis oxytetracycline cryptic metabolites aktinomicete Streptomyces rimosus tetraciklini biosinteza true false true Angleški jezik Slovenski jezik Neznano 2024-08-07 12:38:57 2024-08-07 12:38:58 2024-08-08 04:07:53 0000-00-00 00:00:00 2024 0 0 Soavtorji: Lucija Slemc, Martina Avbelj, Miha Tome, Martin Šala, Paul Herron, Maksym Shmatkov, Marko Petek, Špela Baebler, Peter Mrak, Daslav Hranueli, Antonio Starčević, Iain S. Hunter, Hrvoje Petković; Nasl. z nasl. zaslona; Opis vira z dne 4. 4. 2024; str. 1-30 ǂiss.ǂ5 Vol. 9 May 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 2024-05-01 604.4:579.873.7 2379-5077 10.1128/msystems.00250-24 191381251 https://journals.asm.org/doi/10.1128/msystems.00250-24 1 7fccfc70-5498-11ef-b487-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=28225 RAZ_Psenicnik_Alen_2024.pdf RAZ_Psenicnik_Alen_2024.pdf 1 5C99E1F123A096EA27BD5AE2B3BF1D56 ead9be02393040b8ef71934e9dc1a101d0bfe0cce82406bd6e4094eca5bf9ad1 9eac9bfe-5498-11ef-b487-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=28226 https://doi.org/10.1128/msystems.00250-24 0 ad43be0c-5498-11ef-b487-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=28227 Nacionalni inštitut za biologijo 0 0 0