Deregulation of translation due topost-transcriptional modification of rRNAexplains why erm genes are inducible

摘要

A key mechanism of bacterial resistance to macrolide antibiotics is the dimethylationof a nucleotide in the large ribosomal subunit by erythromycin resistance methyltransferases.The majority of erm genes are expressed only when the antibiotic is present and theerythromycin resistance methyltransferase activity is critical for the survival of bacteria.Although these genes were among the first discovered inducible resistance genes, themolecular basis for their inducibility has remained unknown. Here we show that erythromycinresistance methyltransferase expression reduces cell fitness. Modification of the nucleotide inthe ribosomal tunnel skews the cellular proteome by deregulating the expression of a set ofproteins. We further demonstrate that aberrant translation of specific proteins resultsfrom abnormal interactions of the nascent peptide with the erythromycin resistancemethyltransferase-modified ribosomal tunnel. Our findings provide a plausible explanationwhy erm genes have evolved to be inducible and underscore the importance of nascentpeptide recognition by the ribosome for generating a balanced cellular proteome.