Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus

Pšeničnik, Alen (author), Slemc, Lucija (author), Avbelj, Martina (author), Tome, Miha (author), Šala, Martin (author), Herron, Paul R. (author), Shmatkov, Maksym (author), Petek, Marko (author), Baebler, Špela (author), Mrak, Peter (author), Hranueli, Daslav (author), Starčević, Antonio (author), Hunter, Iain S. (author), Petković, Hrvoje (author)

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.

• Language: English
• Keywords: genome reduction, antibiotic biosynthesis, oxytetracycline, cryptic metabolites
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 30 str.
• Numbering: Vol. 9, iss. 5, art. e00250-24
• PID: 20.500.12556/RUL-164659
• UDC: 604.4:579.873.7
• ISSN on article: 2379-5077
• DOI: 10.1128/msystems.00250-24
• COBISS.SI-ID: 191381251
• Publication date in RUL: 06.11.2024

Record is a part of a journal

• Title: mSystems
• Shortened title: mSystems
• Publisher: American Society for Microbiology
• ISSN: 2379-5077
• COBISS.SI-ID: 525849369

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: aktinomicete, Streptomyces rimosus, tetraciklini, biosinteza