title: Lincomycin at Subinhibitory Concentrations Potentiates Secondary Metabolite Production by Streptomyces spp.
abstract: Antibiotics have either bactericidal or bacteriostatic activity. However, they also induce considerable gene expression in bacteria when used at subinhibitory concentrations (below the MIC). We found that lincomycin, which inhibits protein synthesis by binding to the ribosomes of Gram-positive bacteria, was effective for inducing the expression of genes involved in secondary metabolism in Streptomyces strains when added to medium at subinhibitory concentrations. In Streptomyces coelicolor A3(2), lincomycin at 1/10 of its MIC markedly increased the expression of the pathway-specific regulatory gene actII-ORF4 in the blue-pigmented antibiotic actinorhodin (ACT) biosynthetic gene cluster, which resulted in ACT 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 that were not detected in cells grown in lincomycin-free medium. Bioassay and mass spectrometry analysis revealed that some antibacterial compounds were novel congeners of calcium-dependent antibiotics. Our results indicate that lincomycin at subinhibitory concentrations 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. In addition to these findings, we also report that lincomycin used at concentrations for markedly increased ACT production resulted in alteration of the cytoplasmic protein (FoF1 ATP synthase α and β subunits, etc.) profile and increased intracellular ATP levels. A fundamental mechanism for these unique phenomena is also discussed.
authors.affiliation: Interdisciplinary Graduate School of Science and Technology, Shinshu University, Nagano, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Central Research Laboratory, Nippon Suisan Kaisha, Ltd., Tokyo Innovation Center, Tokyo, Japan.
authors.forename: Seizo
authors.initials: S
authors.lastname: Sato
authors.affiliation: Hiroshima Institute of Technology, Department of Life Science, Hiroshima, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Hiroshima Institute of Technology, Department of Life Science, Hiroshima, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Ochi
authors.affiliation: Department of Bioscience of Biotechnology, Faculty of Agriculture, Shinshu University, Nagano, Japan Department of Interdisciplinary Genome Sciences and Cell Metabolism, Institute for Biomedical Sciences, Shinshu University, Nagano, Japan thosaka@shinshu-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hosaka
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D003470:Culture Media / Q000737:chemistry; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D008034:Lincomycin / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D010860:Pigments, Biological / Q000378:metabolism; D064210:Secondary Metabolism / Q000187:drug effects*; D013057:Spectrum Analysis; D013302:Streptomyces / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D003470:Culture Media; D010860:Pigments, Biological; D008034:Lincomycin
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