title: Revisiting the mechanism of macrolide-antibiotic resistance mediated by ribosomal protein L22.
abstract: Bacterial antibiotic resistance can occur by many mechanisms. An intriguing class of mutants is resistant to macrolide antibiotics even though these drugs still bind to their targets. For example, a 3-residue deletion (DeltaMKR) in ribosomal protein L22 distorts a loop that forms a constriction in the ribosome exit tunnel, apparently allowing nascent-chain egress and translation in the presence of bound macrolides. Here, however, we demonstrate that DeltaMKR and wild-type ribosomes show comparable macrolide sensitivity in vitro. In Escherichia coli, we find that this mutation reduces antibiotic occupancy of the target site on ribosomes in a manner largely dependent on the AcrAB-TolC efflux system. We propose a model for antibiotic resistance in which DeltaMKR ribosomes alter the translation of specific proteins, possibly via changes in programmed stalling, and modify the cell envelope in a manner that lowers steady-state macrolide levels.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. semoore@mail.ucf.edu
authors.forename: Sean D
authors.initials: SD
authors.lastname: Moore
authors.forename: Robert T
authors.initials: RT
authors.lastname: Sauer
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004917:Erythromycin / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D018942:Macrolides / Q000494:pharmacology*; D012269:Ribosomal Proteins / Q000502:physiology*
chemical_list: D017931:DNA Primers; D018942:Macrolides; D012269:Ribosomal Proteins; D004917:Erythromycin