Activation of silent biosynthetic pathways and discovery of novel secondary metabolites in actinomycetes by co-culture with mycolic acid-containing bacteria

  • Shotaro Hoshino
  • Hiroyasu OnakaEmail author
  • Ikuro AbeEmail author
Natural Products - Mini Review


Bacterial secondary metabolites (SM) are rich sources of drug leads, and in particular, numerous metabolites have been isolated from actinomycetes. It was revealed by recent genome sequence projects that actinomycetes harbor much more secondary metabolite-biosynthetic gene clusters (SM-BGCs) than previously expected. Nevertheless, large parts of SM-BGCs in actinomycetes are dormant and cryptic under the standard culture conditions. Therefore, a widely applicable methodology for cryptic SM-BGC activation is required to obtain novel SM. Recently, it was discovered that co-culturing with mycolic-acid-containing bacteria (MACB) widely activated cryptic SM-BGCs in actinomycetes. This “combined-culture” methodology (co-culture methodology using MACB as the partner of actinomycetes) is easily applicable for a broad range of actinomycetes, and indeed, 33 novel SM have been successfully obtained from 12 actinomycetes so far. In this review, the development, application, and mechanistic analysis of the combined-culture method were summarized.


Actinomycetes Secondary metabolites (SM) Mycolic acid-containing bacteria (MACB) Combined culture Secondary metabolite-biosynthetic gene clusters (SM-BGCs) 



This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, JSPS KAKENHI Grant nos. JP16H06443 (to I.A.) and JP18H02120 (to H.O.), JST/NSFC Strategic International Collaborative Research Program (to I.A.), Institute for Fermentation (IFO), Osaka (to H.O.), Amano Enzyme, Inc (to H.O.), JSPS A3 Foresight Program (to H.O.), and JSPS Research Fellowships for Young Scientists (to S.H.). We would like to thank Dr. Shumpei Asamizu (The University of Tokyo) for providing useful advices, and graphical data used in the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Society for Industrial Microbiology and Biotechnology 2018

Authors and Affiliations

  1. 1.Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
  2. 2.Graduate School of Agricultural and Life SciencesThe University of TokyoTokyoJapan
  3. 3.Collaborative Research Institute for Innovative Microbiology, The University of TokyoTokyoJapan

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