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Antibiotic treatment failure in <i>Staphylococcus aureus</i> infections is frequently associated with antimicrobial resistance or the emergence of small-colony variants (SCVs), a metabolically quiescent phenotype that complicates infection management.Here, we show that ciprofloxacin induces a stable SCV phenotype in <i>S. aureus</i>, characterized by reduced colony size, impaired growth, attenuated virulence, and prolonged persistence. Integrated genomic, transcriptomic, and metabolomic analyses revealed that ciprofloxacin-induced SCVs harbor a<i> tal</i> (transaldolase) mutation, which disrupts glycolytic and pentose phosphate pathway flux, depleting pyruvate and tricarboxylic acid cycle intermediates and collapsing ATP biosynthesis. This metabolic disruption leads to nutrient stress and energy limitation,further compounded by a <i>relA</i> mutation that elevates (p)ppGpp accumulation and activates the stringent response.The combined effects of <i>tal</i>- and <i>relA</i>-mediated reprogramming drive metabolic quiescence and the SCV state. Notably, ciprofloxacin-induced SCVs exhibited collateral sensitivity to aminoglycosides both <i>in vitro</i> and <i>in vivo</i>, suggesting that metabolic trade-offs accompanying the stringent response could be therapeutically exploited.These findings define how ciprofloxacin-induced metabolic disruption and stringent response activation cooperatively drive persistent SCV formation in <i>S. aureus</i>, providing new opportunities to overcome antibiotic persistence.