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Antonie van Leeuwenhoek

, Volume 111, Issue 5, pp 705–716 | Cite as

A possible mechanism for lincomycin induction of secondary metabolism in Streptomyces coelicolor A3(2)

  • Misaki Ishizuka
  • Yu Imai
  • Keiichiro Mukai
  • Kazuma Shimono
  • Ryoko Hamauzu
  • Kozo Ochi
  • Takeshi Hosaka
Original Paper

Abstract

Lincomycin forms cross-links within the peptidyl transferase loop region of the 23S ribosomal RNA (rRNA) of the 50S subunit of the bacterial ribosome, which is the site of peptide bond formation, thereby inhibiting protein synthesis. We have previously reported that lincomycin at concentrations below the minimum inhibitory concentration potentiates the production of secondary metabolites in actinomycete strains, suggesting that activation of these strains by utilizing the dose-dependent response of lincomycin could be used to effectively induce the production of cryptic secondary metabolites. Here, we aimed to elucidate the fundamental mechanisms underlying lincomycin induction of secondary metabolism in actinomycetes. In the present study, the dose-dependent response of lincomycin on gene expression of the model actinomycete Streptomyces coelicolor A3(2) and possible relationships to secondary metabolism were investigated. RNA sequencing analysis indicated that lincomycin produced enormous changes in gene expression profiles. Moreover, reverse transcription PCR and/or comparative proteome analysis revealed that in S. coelicolor A3(2), lincomycin, which was used at concentrations for markedly increased blue-pigmented antibiotic actinorhodin production, rapidly enhanced expression of the gene encoding the lincomycin-efflux ABC transporter, the 23S rRNA methyltransferase, and the ribosome-splitting factor to boost the intrinsic lincomycin resistance mechanisms and to reconstruct the probably stalled 70S ribosomes with lincomycin; and in contrast temporarily but dramatically reduced mRNA levels of housekeeping genes, such as those encoding FoF1 ATP synthase, RNA polymerase, ribosomal proteins, and transcription and translation factors, with an increase in intracellular NTPs. A possible mechanism for lincomycin induction of secondary metabolism in S. coelicolor A3(2) is discussed on the basis of these results.

Keywords

Lincomycin Ribosome-targeting antibiotics Antibiotic hormesis Secondary metabolism Streptomyces 

Notes

Acknowledgements

This work was financially supported by a Grant-in-Aid for Young Scientists (A) to Takeshi Hosaka from the Japan Society for the Promotion of Science (Grant No. 25712008).

Conflict of interest

The authors declare that they have no conflict interest.

Supplementary material

10482_2018_1021_MOESM1_ESM.pptx (125 kb)
Supplementary material 1 (PPTX 116 kb)
10482_2018_1021_MOESM2_ESM.docx (110 kb)
Supplementary material 2 (DOCX 110 kb)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Interdisciplinary Genome Science and Cell MetabolismInstitute for Biomedical Science, Shinshu UniversityNaganoJapan
  2. 2.Department of Biomedical Engineering, Graduate School of Science and TechnologyShinshu UniversityNaganoJapan
  3. 3.Department of Biology, Antimicrobial Discovery CenterNortheastern UniversityBostonUSA
  4. 4.Faculty of AgricultureShinshu UniversityNaganoJapan
  5. 5.Department of Life ScienceHiroshima Institute of TechnologyHiroshimaJapan

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