Riboswitching Off Bacterial Growth DOI: 10.1038/Nrmicro1603 Current Antibiotics Target Just Four 5′-Untranslated Regions of Bacterial in in Vitro Cultures of B

RESEARCH HIGHLIGHTS

ANTIMICROBIALS Riboswitching off bacterial growth DOI: 10.1038/nrmicro1603 Current antibiotics target just four 5′-untranslated regions of bacterial In in vitro cultures of B. subtilis, five cellular processes, and bacteria mRNAs and form receptors that of the analogues (tested at 100 µM URLs have found ways to compensate bind specific metabolites, leading concentrations) slowed bacterial Bacillus subtilis for them all. New drugs with novel to the expression of genes involved growth, and three of these analogues http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=genome mechanisms of action are therefore in metabolite biosynthesis and completely inhibited bacterial prj&cmd=Retrieve&dopt=Over urgently needed. But identifying drug transport. Blount et al. proposed that growth for 24 hours. A reporter-gene view&list_uids=17579 targets that are essential for bacterial blocking riboswitch binding could assay measuring β-galactosidase survival, are conserved across species halt the expression of these essential expression under control of the lysC and that lack a human homologue is genes. riboswitch in B. subtilis showed that a significant challenge. Lysine riboswitches are found the analogues exert their effects by Thankfully it seems that in many species of bacteria and repressing lysC at concentrations bacteria still have some essential are known to downregulate two similar to the minimal inhibitory survival pathways that we have not important proteins: a lysine-specific concentrations required to inhibit yet exploited. Writing in Nature importer and aspartokinase II, the bacterial growth. Chemical Biology, Blount et al. initiating enzyme in a biosynthetic Strains of B. subtilis that were provide evidence that bacterial pathway that generates precursors cultivated to be resistant to one of the riboswitches — RNA structures that of cell-wall biosynthesis and spore analogues were found to have a single function as metabolic sensors and formation. The authors therefore point mutation in the lysC ribo- regulate gene expression accordingly designed a series of lysine analogues switch, but not in the yvsH gene that — could represent one such novel aimed at inhibiting lysine ribo- encodes the lysine transporter. This, class of antibiotic target. switches and interfering with this and the observation that mutation of Riboswitches are found in the pathway. the riboswitch conferred resistance to The aim was to find lysine other antibacterial lysine analogues, analogues that showed specificity confirms that the antibacterial activ- for the lysine riboswitch but were ity of the analogues can be attributed sufficiently chemically different to to lysine riboswitch-mediated repres- lysine itself that they did not interact sion of aspartokinase II. with host enzymes or function as a The authors warn that compensa- nutritional source for the bacterium. tory mechanisms might exist that Twelve analogues were tested for will enable bacteria to glean lysine their capacity to bind to the lysine from the host. However, this initial riboswitch of Bacillus subtilis. The study certainly acts as a proof of different specificities attributed to principle for the strategy of targeting various analogues provided useful riboswitches and warrants further insights into the mechanism of ribo- investigation into the development of switch–ligand binding and identified novel antibacterial drugs. molecular features that are essential Joanna Owens, Senior Editor, for ligand recognition. Nature Reviews Drug Discovery Having established that the analogues bind to the riboswitch, ORIGINAL RESEARCH PAPER Blount, K. F. et al. Antibacterial lysine analogs that target lysine the authors then studied whether riboswitches. Nature Chem. Biol. 3, 44–49 (2007). they could inhibit bacterial growth.