Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors
| Autor: | Jamie H. D. Cate, Roger B. Altman, Peter Doig, Ed T. Buurman, D. Bryan Prince, Steven L. Kazmirski, Alexis I. Cocozaki, Scott C. Blanchard, Jian Huang, Andrew D. Ferguson |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Tetracycline 030106 microbiology Biology Ribosome 03 medical and health sciences 23S ribosomal RNA Drug Resistance Bacterial medicine Escherichia coli 30S Genetics Protein Synthesis Inhibitors Multidisciplinary Amino Acids Diamino Translation (biology) Ribosomal RNA Biological Sciences TRNA binding Ribosomal binding site Anti-Bacterial Agents RNA Bacterial 030104 developmental biology RNA Ribosomal Mutation Ribosomes medicine.drug |
| Popis: | Mutations conferring resistance to translation inhibitors often alter the structure of rRNA. Reduced susceptibility to distinct structural antibiotic classes may, therefore, emerge when a common ribosomal binding site is perturbed, which significantly reduces the clinical utility of these agents. The translation inhibitors negamycin and tetracycline interfere with tRNA binding to the aminoacyl-tRNA site on the small 30S ribosomal subunit. However, two negamycin resistance mutations display unexpected differential antibiotic susceptibility profiles. Mutant U1060A in 16S Escherichia coli rRNA is resistant to both antibiotics, whereas mutant U1052G is simultaneously resistant to negamycin and hypersusceptible to tetracycline. Using a combination of microbiological, biochemical, single-molecule fluorescence transfer experiments, and X-ray crystallography, we define the specific structural defects in the U1052G mutant 70S E. coli ribosome that explain its divergent negamycin and tetracycline susceptibility profiles. Unexpectedly, the U1052G mutant ribosome possesses a second tetracycline binding site that correlates with its hypersusceptibility. The creation of a previously unidentified antibiotic binding site raises the prospect of identifying similar phenomena in antibiotic-resistant pathogens in the future. |
| Databáze: | OpenAIRE |
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