RT Journal Article
SR Electronic
T1 Detuning of the Ribosome Conformational Landscape Promotes Antibiotic Resistance and Collateral Sensitivity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.06.13.544509
DO 10.1101/2023.06.13.544509
A1 Mesa, Pablo
A1 Jiménez-Fernández, Alicia
A1 Rosa, Ruggero La
A1 Espinosa, Rocio
A1 Johansen, Helle Krogh
A1 Molin, Søren
A1 Montoya, Guillermo
YR 2023
UL http://biorxiv.org/content/early/2023/06/13/2023.06.13.544509.abstract
AB Around 50% of the current antibiotic arsenal targets the ribosome, thus resistance to ribosome-targeting antibiotics poses severe challenges to antimicrobial treatments. Here, we characterize a 12-nucleotide deletion in the rplF gene encoding the uL6 ribosomal protein, which was identified in a tobramycin-resistant strain of Pseudomonas aeruginosa isolated from a cystic fibrosis patient. To understand this resistance, we determined 87 cryo-EM structures of wild-type and mutant ribosomes characterizing their conformational landscape. Our analysis reveals how detuning of the ribosome dynamics alters its rotational movement circumventing tobramycin inhibition. The mutation compromises the 50S assembly, triggering structural instability and inducing a different rotational dynamic of the 70S. We found 4 new binding sites of tobramycin, one of them exclusive of the mutant, where the binding of the antibiotic acts as an allosteric activator skipping inhibition. Our data also illustrate how chloramphenicol stabilizes the mutant ribosome, enhancing inhibition and thereby leading to collateral sensitivity.Competing Interest StatementDECLARATIONS OF INTEREST Guillermo Montoya declares that is a member of the SAB and a stockholder of Ensoma. The rest of the authors declare no competing financial interests.