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Erythromycin-induced ribosome stall in the ermA leader: a barricade to 5'-to-3' nucleolytic cleavage of the ermA transcript.

Department of Pharmacology, University of Wisconsin Medical School, Madison 53706.

ABSTRACT

The Staphylococcus aureus ermA gene, whose product confers resistance to the macrolide-lincosamide-streptogramin B family of antibiotics, is induced at the level of translation by nanomolar concentrations of erythromycin. Erythromycin also specifically stabilizes ermA transcripts, and the induced stabilization requires in-phase translation of at least one of two small leader peptides in the 5' leader region of the transcript. Erythromycin-induced mRNA stabilization was tested in three constructions in which the ermA transcript was elongated by making insertions at the ermA transcription start. Whereas mRNA downstream of the leader peptide is stabilized by erythromycin, mRNA upstream is not. In the presence of erythromycin, specific mRNA decay intermediates in both the extended ermA genes and the wild-type ermA gene were detected by both Northern blotting and S1 nuclease mapping. The 5' ends of the intermediates map to the sequences that encode each of the two ermA leader peptides, suggesting that the intermediates are produced by stalled erythromycin-bound ribosomes acting as barricades to degradation by 5'-to-3' RNases. In addition, whereas erythromycin was found previously to stabilize ermA transcripts only physically, an ermC-cat-86 hybrid transcript was stabilized both physically and functionally by erythromycin.

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