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Nucleic Acids Res. 2017 Sep 29;45(17):10242-10258. doi: 10.1093/nar/gkx663.

Direct modulation of T-box riboswitch-controlled transcription by protein synthesis inhibitors.

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Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece.
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, 50 South Drive, Bethesda, MD 20892, USA.
Institute of Biosciences and Applications, National Centre for Scientific Research 'Demokritos', Athens, Greece.


Recently, it was discovered that exposure to mainstream antibiotics activate numerous bacterial riboregulators that control antibiotic resistance genes including metabolite-binding riboswitches and other transcription attenuators. However, the effects of commonly used antibiotics, many of which exhibit RNA-binding properties, on the widespread T-box riboswitches, remain unknown. In Staphylococcus aureus, a species-specific glyS T-box controls the supply of glycine for both ribosomal translation and cell wall synthesis, making it a promising target for next-generation antimicrobials. Here, we report that specific protein synthesis inhibitors could either significantly increase T-box-mediated transcription antitermination, while other compounds could suppress it, both in vitro and in vivo. In-line probing of the full-length T-box combined with molecular modelling and docking analyses suggest that the antibiotics that promote transcription antitermination stabilize the T-box:tRNA complex through binding specific positions on stem I and the Staphylococcal-specific stem Sa. By contrast, the antibiotics that attenuate T-box transcription bind to other positions on stem I and do not interact with stem Sa. Taken together, our results reveal that the transcription of essential genes controlled by T-box riboswitches can be directly modulated by commonly used protein synthesis inhibitors. These findings accentuate the regulatory complexities of bacterial response to antimicrobials that involve multiple riboregulators.

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