Ribosome-targeting antibiotics at subinhibitory concentrations potentiate secondary metabolite production by streptomycetes
Takeshi Hosaka1, Kozo Ochi2
1 Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
2 Hiroshima Institute of Technology, Hiroshima, Japan
Antibiotics have bacterial or bacteriostatic activity but induce considerable gene expression in bacteria at subinhibitory concentrations (below the MIC)[1, 2]. We found that secondary metabolite production by Streptomyces spp. was profoundly induced by exposure to ribosome-targeting antibiotics as concentrations below its MIC and the effect of lincomycin was particularly pronounced[3]. In S. coelicolor A3(2), lincomycin at 1/10 of its MIC resulted in a marked increase in the expression of the pathway-specific regulatory gene actII-ORF4, which accounted for blue-pigmented antibiotic actinorhodin overproduction. Intriguingly, S. lividans 1326 grown in the presence of lincomycin at a subinhibitory concentration (1/12 or 1/3 of its MIC) produced abundant antibacterial compounds, including novel congeners of calcium-dependent antibiotics, which were barely produced without lincomycin. These results indicate that lincomycin at concentrations below its MIC potentiates the production of secondary metabolites in Streptomyces strains and suggest that activating these strains by utilizing the dose-response effects of lincomycin could be used to effectively induce the production of cryptic secondary metabolites and to explore new bioactive compounds. In this presentation, I will also talk about a fundamental mechanism for these unique phenomena raised by ribosome-targeting antibiotics.
References
[1] Davies J. et al. Curr Opin Microbiol 9:445-453 (2006).
[2] Yim G. et al. Int J Med Microbiol 296:163-170 (2006).
[3] Imai Y. et al. Appl Environ Microbiol 81:3869-3879 (2015).