Antibiotic resistance (ARE) ABCF proteins are widespread, genome-encoded resistance factors in Gram-positive bacteria that rescue ribosomes stalled by antibiotics. In this study, we integrate genetic, proteomic, metabolomic, and biochemical approaches to reveal that ARE5 subfamily proteins, TiaA and Are5sc, leverage their resistance functions to regulate responses to lincosamides, streptogramins A, and pleuromutilins (LSaP) in Streptomyces coelicolor. While both Are5sc and TiaA are critical for the activation of actinorhodin production in response to LSaP antibiotics, they play distinct roles at the proteome level, determined by their differing resistance profiles and temporally regulated expression. This expression is transcriptionally induced by LSaP antibiotics via an attenuation mechanism and is reciprocally fine-tuned by the resistance functions of the ARE5 paralogs reflecting the specific type and concentration of the antibiotic. Are5sc modulates early adaptive responses by fine-tuning the WblC regulon across a broad range of antibiotic concentrations. In contrast, TiaA is induced later, at higher antibiotic concentrations, where it suppresses global antibiotic stress responses, specifically targeting pleuromutilins produced by higher fungi, reflecting a distinct ecological context compared to lincosamides and streptogramins, which are primarily produced by actinomycetes. Our study provides the first example of ARE ABCF proteins shaping antibiotic response at the translational level, expanding our understanding of the regulatory functions of these ubiquitous proteins.