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Challenging the Traditional Dormancy Assumption: Antibiotic Persisters are Metabolically Active, Non-Growing Cells

ABSTRACT: Bacterial persisters are a subpopulation of multidrug-tolerant cells capable of surviving and resuming activity after exposure to lethal antibiotic treatments, contributing to relapsing infections and the development of antibiotic resistance. We challenge the conventional view that persisters are metabolically dormant by providing compelling evidence that an isogenic population of Escherichia coli remains metabolically active in persistence. Our transcriptomic analysis, conducted at various time points following exposure to lethal concentrations of ampicillin (Amp), revealed a number of genes with differential expression over time. Some genes were consistently upregulated in Amp treated persisters compared to the untreated controls, a change that can only occur in metabolically active cells capable of increasing RNA levels. Some of these genes have been previously linked to persister cells, while others have not been associated with them before. If persister cells were metabolically dormant, we would expect minimal changes in the gene network across different time points of Amp treatment. However, network analysis revealed major shifts in gene network activity at various time points of antibiotic exposure. To explore gene activation in persisters, we developed a new promoter system in which an Amp resistance gene is activated specifically in persister cells. Following treatment with lethal Amp, the Amp resistance gene conferred resistance after ~8 h. This gene’s activation requires the production of both mRNA and protein, processes that can only occur in metabolically active cells. These findings reveal that persisters are metabolically active, non-dividing cells, thereby challenging the notion that they are dormant.

ORGANISM(S): Escherichia coli

PROVIDER: GSE278938 | GEO | 2025/10/06

REPOSITORIES: GEO

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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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Challenging the Traditional Dormancy Assumption: Antibiotic Persisters are Metabolically Active, Non-Growing Cells

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