Insights into the mechanism of antibiotic and toxin inhibition of ribosome function and antibiotic-resistant ribosomal subunits, using X-ray crystallography.

• Applicant: Professor Dr. Daniel Nicodemus Wilson
• Subject Area: Structural Biology
• Term: from 2007 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34302568

The protein synthesizing apparatus, the ribosome, is one of the major targets for antibiotics within the cell. Many clinically important classes of antibiotics, such as macrolides (erythromycin), tetracyclines and chloramphenicols, target the small or large subunit of the ribosome. The ever-increasing emergence of antibiotic-resistant bacteria has restricted the medical usage of many antibiotics and led to the development of novel or improved inhibitors. Structures of such novel or improved drugs in complex with their target, the ribosome, will not only lead to an understanding into the mechanism of inhibition, but will also open the door to design of better antimicrobial agents. Additionally, structures of antibiotic-resistant bacterial ribosomes will be determined, in the presence and absence of the drug, providing insight into how alterations within the ribosomal components confer high-level antibiotic resistance, even in circumstances where the drug still binds. In addition to antibiotics, toxins, such as RelE, target the ribosome. Structures of these toxins in complex with their ribosomal substrate will shed light into their mechanism of action. Finally, small differences between ribosomes from different organisms leads to slight differences in drug binding, suggesting that antibioticribosome structures should utilize ribosomes from pathogenic, or closely related, species. Thus, crystallization of the large ribosomal subunit from Bacillus species will be improved in order to determine clinical relevant ribosome-antibiotic complexes.

• DFG Programme: Research Grants