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Ciprofloxacin-induced metabolic disruption and stringent response drives persistent small-colony variants in Staphylococcus aureus

ABSTRACT:

Antibiotic treatment failure in Staphylococcus aureus 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 S. aureus, 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 tal (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 relA mutation that elevates (p)ppGpp accumulation and activates the stringent response. The combined effects of tal- and relA-mediated reprogramming drive metabolic quiescence and the SCV state. Notably, ciprofloxacin-induced SCVs exhibited collateral sensitivity to aminoglycosides both in vitro and in vivo, 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 S. aureus, providing new opportunities to overcome antibiotic persistence.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13343 | MetaboLights | 2025-11-19

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13343_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13343_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13343_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13343_LC-MS_positive_reverse-phase_metabolite_profiling_v10_maf.tsv	Tabular

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Project description:Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistances. Even antibiotic susceptible S. aureus can survive antibiotic therapy and persist, requiring prolonged treatment and surgical interventions. These so-called persisters display an arrested-growth phenotype, tolerate high antibiotic concentrations and are associated with chronic and recurrent infections. To characterize these persisters, we assessed S. aureus recovered directly from a patient suffering from a persistent infection. We show that host-mediated stress, including acidic-pH, abscesses-environment, and antibiotic exposure promoted persister formation in-vitro and in-vivo. Multi-omics analysis identified molecular changes in S. aureus in response to acid-stress leading to an overall virulent population. However, further analysis of a persister-enriched population revealed major molecular reprogramming in persisters including downregulation of virulence and cell division, and upregulation of ribosomal proteins, nucleotide-, and amino acid- metabolic pathways, suggesting their requirement to fuel and maintain the persister phenotype and highlighting that persisters are not completely metabolically inactive. Additionally, decreased aconitase activity and ATP-levels and accumulation of insoluble proteins involved in transcription, translation and energy-production correlated with persistence in S. aureus, underpinning the molecular mechanisms that drive the persister phenotype. Upon regrowth, these persisters regained their virulence potential and metabolically active phenotype including reduction of insoluble proteins, exhibiting a reversible state, crucial for recurrent infections. We further show that a targeted anti-persister combination therapy using retinoid derivatives and antibiotics significantly reduced lag-phase heterogeneity and persisters in a murine infection model. Our results provide molecular insights into persisters and help explain why persistent S. aureus infections are so difficult-to-treat.

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Ciprofloxacin-induced metabolic disruption and stringent response drives persistent small-colony variants in Staphylococcus aureus

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