Erythromycin resistance by L4/L22 mutations and resistance masking by drug efflux pump deficiency.
We characterized the effects of classical erythromycin resistance mutations in ribosomal proteins L4 and L22 of the large ribosomal subunit on the kinetics of erythromycin binding. Our data are consistent with a mechanism in which the macrolide erythromycin enters and exits the ribosome through the nascent peptide exit tunnel, and suggest that these mutations both impair passive transport through the tunnel and distort the erythromycin-binding site. The growth-inhibitory action of erythromycin was characterized for bacterial populations with wild-type and L22-mutated ribosomes in drug efflux pump deficient and proficient backgrounds. The L22 mutation conferred reduced erythromycin susceptibility in the drug efflux pump proficient, but not deficient, background. This 'masking' of drug resistance by pump deficiency was reproduced by modelling with input data from our biochemical experiments. We discuss the general principles behind the phenomenon of drug resistance 'masking', and highlight its potential importance for slowing down the evolution of drug resistance among pathogens.
Lovmar
Martin
M
Department of Cell and Molecular Biology, Molecular Biology Program, Uppsala University, Uppsala, Sweden.
Nilsson
Karin
K
Lukk
Eliisa
E
Vimberg
Vladimir
V
Tenson
Tanel
T
Ehrenberg
Måns
M
D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics*; D004917:Erythromycin / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development; D029968:Escherichia coli Proteins / Q000235:genetics*; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics*; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism
D029968:Escherichia coli Proteins; D050505:Mutant Proteins; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; C056368:ribosomal protein L4; C489371:rplV protein, E coli; D004917:Erythromycin