Comparative genomic analysis of Streptomyces rapamycinicus NRRL 5491 and its mutant overproducing rapamycin

Jo, Hee-Geun; Adidjaja, Joshua Julio; Kim, Do Kyung; Park, Bu-Soo; Lee, Namil; Cho, Byung-Kwan; Kim, Hyun Uk; Oh, Min Kyu

doi:10.1038/s41598-022-14199-6

Cited by 6 publications

(3 citation statements)

References 62 publications

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“…As exemplified by S. rimosus and other Streptomyces species, both the frequency and scale of rearrangements can also be induced by mutagenesis or genetic engineering ( 50 , 54 ). Jo et al ( 55 ) demonstrated that a rapamycin-overproducing strain of Streptomyces rapamycinicus , generated by random mutagenesis and strain selection for higher production of rapamycin, underwent spontaneous genome reduction: the 12.47 Mb genome of the native parent strain was reduced to 9.56 Mb in the overproducing strain. A larger gene deletion near one chromosomal end was accompanied by a DNA duplication, containing the entire BGC encoding biosynthesis of rapamycin.…”

Section: Discussionmentioning

confidence: 99%

Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus

Pšeničnik,

Slemc,

Avbelj

et al. 2024

mSystems

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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. IMPORTANCE There is a critical need to develop novel antibiotics to combat antimicrobial resistance. Streptomyces species are very rich source of antibiotics, typically encoding 20–60 biosynthetic gene clusters (BGCs). However, under laboratory conditions, most are either silent or poorly expressed so that their products are only detectable at nanogram quantities, which hampers drug development efforts. To address this subject, we used comparative genome analysis of industrial Streptomyces rimosus strains producing high titers of a broad spectrum antibiotic oxytetracycline (OTC), developed during decades of industrial strain improvement. Interestingly, large-scale chromosomal deletions were observed. Based on this information, we carried out targeted genome deletions in the native strain S. rimosus ATCC 10970, and we show that a targeted deletion in the vicinity of the OTC BGC significantly induced expression of the OTC BGC, as well as some other silent BGCs, thus suggesting that this approach may be a useful way to identify new natural products.

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Section: Discussionmentioning

confidence: 99%

Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus

Pšeničnik,

Slemc,

Avbelj

et al. 2024

mSystems

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“…The procedure for analyzing neoaureothin concentrations was based on a previous study (Peng et al, 2019). Packed mycelium volume was used for biomass determination (Jo et al, 2022; Wu et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

Quorum sensing‐based metabolic engineering of the precursor supply in Streptomyces coelicolor to improve heterologous production of neoaureothin

Kim

et al. 2023

Biotech & Bioengineering

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Streptomyces are important industrial bacteria that produce pharmaceutically valuable polyketides. However, mass production on an industrial scale is limited by low productivity, which can be overcome through metabolic engineering and the synthetic biology of the host strain. Recently, the introduction of an auto‐inducible expression system depending on microbial physiological state has been suggested as an important tool for the industrial‐scale production of polyketides. In this study, titer improvement by enhancing the pool of CoA‐derived precursors required for polyketide production was driven in a quorum sensing (QS)‐dependent manner. A self‐sustaining and inducer‐independent regulatory system, named the QS‐based metabolic engineering of precursor pool (QMP) system, was constructed, wherein the expression of genes involved in precursor biosynthesis was regulated by the QS‐responsive promoter, scbAp. The QMP system was applied for neoaureothin production in a heterologous host, Streptomyces coelicolor M1152, and productivity increased by up to 4‐fold. In particular, the engineered hyperproducers produced high levels of neoaureothin without adversely affecting cell growth. Overall, this study showed that self‐regulated metabolic engineering mediated by QS has the potential to engineer strains for polyketide titer improvement.

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“…Edison et al [31] used in-silico analysis in structural elucidation. Some researchers used comparative genomics in their studies [32][33][34][35][36][37]. Kumar et al [38] used in vitro and insilico analysis using machine learning in their studies.…”

Section: Streptomyces Lividans -Streptomyces Coelicolor Andmentioning

confidence: 99%

Novel Drug Development for Treatment of COVID-19 by In Silico Analysis: Identification of SARS-Cov-2 Inhibiting Streptomyces Compounds

Kumar

Gholap

Pillai

2023

Journal of Cellular Signaling

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In accordance with the present epidemiological paradigm, viral mutations of the virus are on the rise, and their natural effects are being selected for at a higher rate than normal. According to the World Health Organization (WHO), the global COVID-19 pandemic induced by the Delta and Omicron strain of the SARS-CoV-2 virus could propagate and disseminate more rapidly than other viruses thanks to its many mutations, and these also caused some very significant health problems. The established medications would eventually start to lose their efficacy since the variation mutated more quickly than the original stain. As protein spikes are the point of origin or epitome for the mutations to take place, it would be most effective to target the remaining vital enzymes by binding the proteins with the largest pocket sizes. The objective of the current work is to employ in-silico analysis to discover the streptomyces chemicals that suppress the SARS-CoV-2 virus as well as its mutated strains thus promoting a healthy body. Based on the drug likeness property of compounds when subjected to molecular docking, a total of 14 compounds were identified and selected from the PUBCHEM database that showed highest binding energy with the targeted Receptor Binding Domain. The compounds namely - Streptomyces tanashiensis; Thaxtomin A; Bafilomycin A1 from Streptomyces griseus and few others as mentioned further on more research would support and confirm the utilizing of these to create new medications to treat the novel SARS-CoV-2 infectious strains.

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Comparative genomic analysis of Streptomyces rapamycinicus NRRL 5491 and its mutant overproducing rapamycin

Cited by 6 publications

References 62 publications

Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus

Oxytetracycline hyper-production through targeted genome reduction of Streptomyces rimosus

Quorum sensing‐based metabolic engineering of the precursor supply in Streptomyces coelicolor to improve heterologous production of neoaureothin

Novel Drug Development for Treatment of COVID-19 by In Silico Analysis: Identification of SARS-Cov-2 Inhibiting Streptomyces Compounds

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