The expression of many genes is controlled by upstream ORFs (uORFs). Typically, the progression of the ribosome through a regulatory uORF, which depends on the physiological state of the cell, influences the expression of the downstream gene. In the classic mechanism of induction of macrolide resistance genes, antibiotics promote translation arrest within the uORF, and the static ribosome induces a conformational change in mRNA, resulting in the activation of translation of the resistance cistron. We show that ketolide antibiotics, which do not induce ribosome stalling at the uORF of the ermC resistance gene, trigger its expression via a unique mechanism. Ketolides promote frameshifting at the uORF, allowing the translating ribosome to invade the intergenic spacer. The dynamic unfolding of the mRNA structure leads to the activation of resistance. Conceptually similar mechanisms may control other cellular genes. The identified property of ketolides to reduce the fidelity of reading frame maintenance may have medical implications.
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