The use of translation-targeting antibiotics in clinical medicine began in 1948, when the antibiotic streptomycin, derived from soil bacteria, was introduced to combat the spread of tuberculosis in the United States. Today, almost every step of the translation cycle can be targeted by small-molecule antibiotics. However, as for many anti-infective agents, drug-resistant organisms have invariably emerged for each translation inhibitor class. Target modification, including post-transcriptional or post-translational modifications and/or point mutations within the drug binding site, serves as an important drug resistance mechanism.
Therapies targeting the translation apparatus remain in widespread use, and new strategies for targeting the components of translation continue to be pursued. A key reason for this is that protein synthesis plays a ubiquitous and central role in all forms of life and the inhibition of translation is a proven strategy for broad spectrum bacterial growth inhibition. We use smFRET do characterize and determine the mechanism of action of the translation-targeting class of antibiotics known as aminoglycosides.
Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome. Olivier NB, Altman RB, Noeske J, Basarab GS, Code E, Ferguson AD, Gao N, Huang J, Juette MF, Livchak S, Miller MD, Prince DB, Cate JH, Buurman ET, Blanchard SC. PNAS (2014) 111(46):16274-16279.
Allosteric Control of the Ribosome by Small-molecule Antibiotics. Wang L., Pulk A., Wasserman MR., Feldman MB., Altman RB., Doudna Cate JH., Blanchard SC., NATURE STRUCTURAL & MOLECULAR BIOLOGY (2012): doi: 10.1038/nsmb.2360.
Mechanistic insights into antibiotic action on the ribosome through single-molecule fluorescence imaging. Wang L, Wasserman MR, Feldman MB, Altman RB, Blanchard SC, ANNALS OF THE NEW YORK ACADEMY OF SCIENCES (2011) doi: 10.1111/j. 1749-6632.2012.x
Aminoglycoside Activity Observed on Single Pre-translocation Ribosome Complexes. Feldman MB, Terry DS, Altman RB, Blanchard SC; NATURE CHEM BIOL (2010) Vol. 6(1): 54-62. PMID: 19946275.