Dynamic interplay between chloramphenicol/linezolid and the translating ribosome

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The projects of P4 (Wilson) address the dynamic interplay between antibiotics and the translational apparatus. In the first period, the Wilson group focused on the clinically important class of tetracycline antibiotics. Key achievements include a structural and biochemical characterization of improved tetracycline derivatives, identifying chemical aspects of the drug that improve the inhibitory activity as well as overcoming TetM-mediated tetracycline resistance. In addition, we present a near-atomic resolution structure of the tetracycline-resistance protein TetM in complex with the ribosome (in collaboration with P3), providing molecular insight into how TetM dislodges the drug from the ribosome to confer tetracycline resistance. In the second period, the Wilson group proposes to address the mechanism of ribosome inhibition and resistance to chloramphenicol and oxazolidinone antibiotics. Specifically, the mechanism by which these drugs interplay with the nascent polypeptide chain to mediate ribosome stalling, and thereby induce expression of downstream resistance genes will be investigated. Additionally, biochemical studies addressing the mechanism of proline stalling initiated in the first period (in collaboration P5 and P6) will be continued, as well as ribosome profiling studies that are in progress with P7 and P8. Collectively, such studies provide mechanistic insight into how diverse ribosomal ligands interplay with the ribosome to modulate the activity of the translational apparatus.