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Effect of fluoroquinolone-induced gyrase cleavage sites on gene expression during drug treatment period and recovery period on E. coli

ABSTRACT: Persisters are rare phenotypic variants that can survive bactericidal doses of antibiotics and resume growth after the conclusion of treatment. They are suspected to be culprits of recurrent infections, and are distinct from resistant mutants because they are genetically identical to bacteria that die from treatment. Persisters to fluoroquinolones (FQs) experience DNA damage from treatment in stationary-phase culture, which suggests that FQs can corrupt their primary target, DNA gyrase, even in these super-tolerant cells. Since DNA damage from FQs originates from its stabilization of DNA gyrase in complexes with cleaved DNA, we hypothesized that the characteristics of FQ-stabilized DNA gyrase cleavage sites (GCS), such as the abundance, and/or location, might be influential to persistence. To test this hypothesis, we measured genome-wide distributions of GCS after treatment with a panel of FQs.We found drug-specific effects on the location and abundances of GCSs and discovered a negative correlation between the number of GCSs and FQ persister levels. Further, additional experiments and analyses suggested that persister levels are not governed by cleavage to a single specific site, but rather survival is a more complex function with respect to GCSs. Together, these findings demonstrate that there are drug specific differences in GCSs that correlate with persister levels, and suggest that the ability of an FQ to stabilize DNA-gyrase complexes at more sites will improve its bactericidal ability.

ORGANISM(S): Escherichia coli

PROVIDER: GSE206609 | GEO | 2022/12/05

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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Effect of fluoroquinolone-induced gyrase cleavage sites on gene expression during drug treatment period and recovery period on E. coli

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