Activation of silent biosynthetic pathways and discovery of novel secondary metabolites in actinomycetes by co-culture with mycolic acid-containing bacteria
- 462 Downloads
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.
KeywordsActinomycetes 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.
- 2.Adnani N, Chevrette MG, Adibhatla SN, Zhang F, Yu Q, Braun DR, Nelson J, Simpkins SW, McDonald BR, Myers CL, Piotrowski JS, Thompson CJ, Currie CR, Li L, Rajski SR, Bugni TS (2017) Coculture of marine invertebrate-associated bacteria and interdisciplinary technologies enable biosynthesis and discovery of a new antibiotic, keyicin. ACS Chem Biol 12:3093–3102CrossRefGoogle Scholar
- 28.Low ZJ, Pang LM, Ding Y, Cheang QW, Le Mai Hoang K, Thi Tran H, Li J, Liu XW, Kanagasundaram Y, Yang L, Liang ZX (2018) Identification of a biosynthetic gene cluster for the polyene macrolactam sceliphrolactam in a Streptomyces strain isolated from mangrove sediment. Sci Rep. https://doi.org/10.1038/s41598-018-20018-8 Google Scholar
- 39.Schulze CJ, Donia MS, Siqueira-Neto JL, Ray D, Raskatov JA, Green RE, McKerrow JH, Fischbach MA, Linington RG (2015) Genome-directed lead discovery: biosynthesis, structure elucidation, and biological evaluation of two families of polyene macrolactams against Trypanosoma brucei. ACS Chem Biol 10:2373–2381CrossRefGoogle Scholar
- 40.Skellam EJ, Stewart AK, Strangman WK, Wright JL (2013) Identification of micromonolactam, a new polyene macrocyclic lactam from two marine Micromonospora strains using chemical and molecular methods: clarification of the biosynthetic pathway from a glutamate starter unit. J Antibiot 66:431–441CrossRefGoogle Scholar
- 41.Slattery M, Rajbhandari I, Wesson K (2001) Competition-mediated antibiotic induction in the marine bacterium Streptomyces tenjimariensis. Microb Ecol 41:90–96Google Scholar