Poster abstracts
Poster number 109 submitted by Yury Polikanov
Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion
Yury Polikanov (University of Illinois at Chicago)
Abstract:
The ribosome is an essential drug target as many classes of clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent mechanisms of resistance to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methylase Cfr. Despite its clinical significance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. In this work, we developed a method to express a functionally-active Cfr-methylase in the thermophilic bacterium Thermus thermophilus and report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-tRNAs. Our structures reveal that an allosteric rearrangement of nucleotide A2062 upon Cfr-methylation of A2503 likely contributes to the reduced potency of some PTC inhibitors, providing additional insights into the Cfr resistance mechanism. Lastly, by determining the structures of the Cfr-methylated ribosome in complex with the antibiotics iboxamycin and tylosin, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome.
Keywords: Ribosome, Structure, Drug-resistance