Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus

• DOI: 10.1128/msystems.00250-24
• Publication Date: 2024-04-02T20:04:47Z
• Authors: Alen Pšeničnik; 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
• Keywords: 570; cryptic metabolites; aktinomicete; genome reduction, antibiotic biosynthesis, oxytetracycline, cryptic metabolites; aktinomicete, Streptomyces rimosus, tetraciklini, biosinteza; Oxytetracycline; Microbiology; Streptomyces rimosus; Streptomyces; Anti-Bacterial Agents; info:eu-repo/classification/udc/604.4:579.873.7; Multigene Family; oxytetracycline; biosinteza; genome reduction; antibiotic biosynthesis; tetraciklini; Genome, Bacterial; info:eu-repo/classification/udc/604; Research Article

ABSTRACT 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 novel there is need develop rapid and efficient strain development approaches. This study uses comparative genome analysis instruct rational improvement, using Streptomyces rimosus , producer antibiotic oxytetracycline (OTC) model system. Sequencing genomes two industrial strains M4018 R6-500, developed independently from common ancestor, identified large DNA rearrangements located at chromosome end. We evaluated effect these deletions on parental S. Type Strain (ATCC 10970) where introduction 145 kb deletion close OTC BGC in resulted massive overproduction, achieving titers that were equivalent R6-500. Transcriptome data supported hypothesis reason for an increase biosynthesis was due enhanced transcription not substrate supply. also observed changes expression other cryptic BGCs; some undetectable ATCC 10970, now produced high titers. demonstrated first time main force behind overexpression rearrangement. new approach demonstrates great potential activate yet unexplored natural products medical value. IMPORTANCE There critical antibiotics combat antimicrobial resistance. species very rich source typically 20–60 (BGCs). However, under laboratory conditions, most expressed so their only detectable nanogram quantities, which hampers drug efforts. To address this subject, we used producing broad spectrum (OTC), during decades improvement. Interestingly, large-scale chromosomal observed. Based information, carried out targeted native show vicinity significantly induced BGC, well BGCs, thus suggesting may be useful way identify products.