title: Antibiotic dialogues: induction of silent biosynthetic gene clusters by exogenous small molecules.
abstract: Natural products have traditionally served as a dominant source of therapeutic agents. They are produced by dedicated biosynthetic gene clusters that assemble complex, bioactive molecules from simple precursors. Recent genome sequencing efforts coupled with advances in bioinformatics indicate that the majority of biosynthetic gene clusters are not expressed under normal laboratory conditions. Termed 'silent' or 'cryptic', these gene clusters represent a treasure trove for discovery of novel small molecules, their regulatory circuits and their biosynthetic pathways. In this review, we assess the capacity of exogenous small molecules in activating silent secondary metabolite gene clusters. Several approaches that have been developed are presented, including coculture techniques, ribosome engineering, chromatin remodeling and high-throughput elicitor screens. The rationale, applications and mechanisms attendant to each are discussed. Some general conclusions can be drawn from our analysis: exogenous small molecules comprise a productive avenue for the discovery of cryptic metabolites. Specifically, growth-inhibitory molecules, in some cases clinically used antibiotics, serve as effective inducers of silent biosynthetic gene clusters, suggesting that old antibiotics may be used to find new ones. The involvement of natural antibiotics in modulating secondary metabolism at subinhibitory concentrations suggests that they represent part of the microbial vocabulary through which inter- and intraspecies interactions are mediated.
authors: Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors: Bethany K
authors: BK
authors: Okada
authors: Department of Chemistry, Princeton University, Princeton, NJ 08544, USA mrseyed@princeton.edu.|Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors: Mohammad R
authors: MR
authors: Seyedsayamdost
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D053898:Biosynthetic Pathways / Q000187:drug effects / Q000235:genetics*; D005810:Multigene Family / Q000235:genetics*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D054852:Small Molecule Libraries
keywords: HiTES; antibiotics; chromatin remodeling; interspecies interaction; ribosome engineering; secondary metabolites