The emergence of acquired resistance continues to undermine the clinical effectiveness of targeted antibiotics. Current strategies predominantly emphasize scaffold diversification against individual targets; however, we investigated whether a conserved ligand-binding mode could overcome resistance across mechanistically distinct targets. By conformationally constraining a linezolid–ciprofloxacin hybrid via a rationally designed linker, we obtained a compound that adopts a unique folded conformation within the ribosomal nascent peptide exit tunnel. High-resolution cryo-EM structures at approximately 2.06 Å resolution reveal that binding is stabilized by a H₂O–Mg²⁺ bridge to the rRNA backbone, along with sandwich-like π-stacking interactions—structurally reminiscent of the quinolone–topoisomerase–DNA complex—thus enabling balanced dual targeting of both the ribosome and topoisomerase. Notably, this pharmacophore unexpectedly engages the resistance-associated residue A2062, transforming the allosteric perturbation induced by cfr methylation from a vulnerability into an exploitable liability, thereby restoring potent inhibitory activity regardless of cfr-mediated A2503 methylation. The hybrid not only retains robust activity in vitro against clinical isolates resistant to both parent antibiotics, but also exhibits broad-spectrum efficacy and significant in vivo activity against WHO high-priority pathogens, including MRSA and VRE. Moreover, modulation of the linker allows precise tuning of pharmacokinetic distribution, enabling selective targeting of either pulmonary or systemic infections. Collectively, these findings demonstrate that leveraging mechanistic convergence in ligand recognition constitutes a powerful chemical strategy to surmount on-target resistance.