Trans-acting regulatory RNAs have the capacity to base pair with more mRNAs than experimentally detected under given conditions. This raises the question whether the sRNA target specificity can change upon metabolic or environmental changes. In Sinorhizobium meliloti, the sRNA rnTrpL is derived from a tryptophan (Trp) transcription attenuator, which is located upstream of the Trp biosynthesis gene trpE(G) and harbors the small ORF trpL. When Trp is available, efficient trpL translation causes transcription termination and liberation of rnTrpL, which then downregulates the trpDC operon. On the other hand, the trpL-encoded leader peptide peTrpL has a Trp-independent role in posttranscriptional regulation of antibiotic resistance. Here, we show that upon tetracycline (Tc) exposure, rnTrpL accumulates independently of Trp availability. Further, we provide evidence that both rnTrpL and peTrpL act together in the Tc-dependent destabilization of rplUrpmA mRNA encoding ribosomal proteins L21 and L27. rnTrpL, peTrpL and rplUrpmA mRNA were copurified in an antibiotic- dependent ribonucleoprotein complex (ARNP). In vitro ARNP reconstitution with competing trpD and rplU transcripts revealed that peTrpL and Tc reprogram the rnTrpL specificity in favor of rplU. In vivo, this probably supports bacterial adaptation to antibiotics. Our findings provide evidence for sRNA reprograming in response to antibiotic exposure.