Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success
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ABSTRACT:
ORGANISM(S): Staphylococcus aureus
PROVIDER: GSE148024 | GEO | 2021/02/12
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.
2021-02-12 | PXD022858 | Pride
Project description:Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistance. 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, abscess environment, and antibiotic exposure promoted persister formation in vitro and in vivo. Multiomics 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 down-regulation of virulence and cell division and up-regulation 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 antipersister 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.
| S-EPMC7896289 | biostudies-literature
Project description:Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success
| PRJNA622829 | ENA
Project description:Persister cells are genetically identical variants in a bacterial population that have phenotypically modified their physiology to survive environmental stress. . To better define general persistence mechanisms that can be targeted to develop anti-persistence therapeutics, we performed transcriptomics analyses of Burkholderia thailandensis enriched for persisters using three methods: flow sorting by low proton motive force, meropenem treatment, and culture aging. Although the three persister populations generally expressed divergent gene expression profiles that underscores the multi-mechanistic nature of persistence, there were several common gene pathways expressed in two or more persister populations, including polyketide and non-ribosomal peptide synthesis, Clp proteases, mobile elements, enzymes involved in the lipid metabolism, and ATP-binding cassette (ABC) transporter systems. In particular, identification of genes that encode for polyketide synthases (PKS) and fatty acid catabolism indicate that generation of secondary metabolites, natural products, and complex lipids are needed for the maintenance of the persistence state. Persisters are markedly reduced in transposon mutants of the PKS gene BTH_I2366. Furthermore, treatment of multiple bacterial pathogens with the fatty acid synthesis inhibitor, CP-640186, potentiated antibiotic efficacy against the persisters. All together, our results suggest that bacterial persisters may exhibit an outward dormant physiology, but maintain active metabolic processes that are required to maintain persistence.
2019-03-06 | GSE127838 | GEO
Project description:Bacterial persistence is a potential cause of antibiotic therapy failure. Antibiotic-tolerant persisters originate from phenotypic differentiation within a susceptible population, occurring with a frequency that can be altered by mutations. Recent studies have proven that persistence is a highly evolvable trait and, consequently, an important evolutionary strategy of bacterial populations to adapt to high-dose antibiotic therapy. Yet, the factors that govern the evolutionary dynamics of persistence are currently poorly understood. Theoretical studies predict far-reaching effects of bottlenecking on the evolutionary adaption of bacterial populations, but these effects have never been investigated in the context of persistence. Bottlenecking events are frequently encountered by infecting pathogens during host-to-host transmission and antibiotic treatment. In this study, we used a combination of experimental evolution and barcoded knockout libraries to examine how population bottlenecking affects the evolutionary dynamics of persistence. In accordance with existing hypotheses, small bottlenecks were found to restrict the adaptive potential of populations and result in more heterogeneous evolutionary outcomes. Evolutionary trajectories followed in small-bottlenecking regimes additionally suggest that the fitness landscape associated with persistence has a rugged topography, with distinct trajectories toward increased persistence that are accessible to evolving populations. Furthermore, sequencing data of evolved populations and knockout libraries after selection reveal various genes that are potentially involved in persistence, including previously known as well as novel targets. Together, our results do not only provide experimental evidence for evolutionary theories, but also contribute to a better understanding of the environmental and genetic factors that guide bacterial adaptation to antibiotic treatment.
| S-EPMC8321523 | biostudies-literature
Project description:Staphylococcus aureus can cause severe invasive infections that require prolonged antibiotic treatment. Although S. aureus can easily acquire antibiotic resistance, even fully susceptible bacteria can persist and survive antibiotic therapy, thus complicating treatment. These so-called persisters are phenotypic variants of bacteria characterized by an arrested-growth phenotype that can tolerate high concentrations of chemotherapeutics and are associated with chronic and recurrent infections. Here, we show that S. aureus recovered directly from infection sites, displayed an increased bacterial lag-phase heterogeneity, forming more non-stable small colonies, indicating the presence of dormant bacteria. Infection modelling showed that host-mediated stress, including acidic pH, neutrophil exposure and murine abscesses, as well as antibiotic treatment, promoted formation of persisters both in vitro and in vivo. Proteomics and RNA-sequencing revealed molecular changes in bacteria in response to acidic stress leading to an overall more virulent population. However, after persister-enrichment, S. aureus displayed downregulation of pathways involved in virulence, cell division, and DNA replication, while ribosomal proteins, nucleotide-, and amino acid- metabolic pathways were upregulated, suggesting their requirement to fuel and maintain the persister phenotype. We demonstrate that decreased aconitase activity and ATP-levels as well as accumulation of insoluble proteins correlated with dormancy and growth reactivation cycles. Combination of antibiotics with retinoid derivatives, especially CD1530, significantly reduced both persisters and total bacterial load in a murine infection model. Our study provides an in-depth characterization of S. aureus persisters and shows that treatment failure due to antibiotic persistence could be addressed by using retinoid derivatives in combination with conventional antibiotics.
2021-09-09 | PXD018372 | Pride
Project description:Antibiotic stewardship programs proved to be effective in improving prescribing appropriateness. This multicenter quasi-experimental study, aimed to assesses the stewardship impact on antibiotics prescribing in different semesters from 2014 to 2019 in three pediatric emergency departments (Center A, B, and C) in Italy. All consecutive patients diagnosed with acute otitis media or pharyngitis were evaluated for inclusion. Two different stewardship were adopted: for Center A and B, clinical pathways were implemented and disseminated, and yearly lectures were held, for Center C, only pathways were implemented. Broad-spectrum prescription rates decreased significantly by 80% for pharyngitis and 29.5 to 55.2% for otitis after the implementation. In Center C, rates gradually increased from the year after the implementation. Amoxicillin dosage adjusted to pharyngitis recommendations in Center C (53.7 vs. 51.6 mg/kg/die; p = 0.011) and otitis recommendations in Center A increasing from 50.0 to 75.0 mg/kg/die (p < 0.001). Days of therapy in children < 24 months with otitis increased from 8.0 to 10.0 in Center A, while in older children decreased in Center A (8.0 vs. 7.0; p < 0.001) and Center B (10.0 vs. 8.0; p < 0.001). Clinical pathways combined with educational lectures is a feasible and sustainable program in reducing broad-spectrum antibiotic prescribing with stable rates over time.
| S-EPMC7761799 | biostudies-literature
Project description:We report identification and characterization of antibiotic persister mutants carrying characteristic mutations in the Escherichia coli rpoB gene
2021-01-26 | GSE165446 | GEO
Project description:Biofilms are heterogeneous bacterial communities featured by high persister prevalence, responsible for antibiotic tolerance. However, the mechanisms underlying persister formation within biofilms remained ambiguous. Here, by developing and utilizing a ribosomal RNA depleted bacterial single-cell RNA-seq method, RiboD-mSPLiT, we resolved biofilm heterogeneity and discovered pdeI as a marker gene for persister subgroup within biofilms. Remarkably, our findings elucidated that PdeI upregulates cellular levels of c-di-GMP, which acts as an antitoxin to modulate the toxicity of toxin protein HipH. HipH localizes on nucleoid and functions as a potent DNase, inducing cells into a viable but non-culturable state. Conversely, c-di-GMP interacts with HipH, reducing its genotoxic effects and enabling cells to enter a persister state, resulting in drug tolerance. Importantly, by targeting this toxin-antitoxin system, we repressed drug tolerance in Uropathogenic Escherichia coli infections, offering promising therapeutic strategies against chronic and relapsing infections.
2024-02-20 | GSE239504 | GEO
Project description:Biofilms are heterogeneous bacterial communities featured by high persister prevalence, responsible for antibiotic tolerance. However, the mechanisms underlying persister formation within biofilms remained ambiguous. Here, by developing and utilizing a ribosomal RNA depleted bacterial single-cell RNA-seq method, RiboD-mSPLiT, we resolved biofilm heterogeneity and discovered pdeI as a marker gene for persister subgroup within biofilms. Remarkably, our findings elucidated that PdeI upregulates cellular levels of c-di-GMP, which acts as an antitoxin to modulate the toxicity of toxin protein HipH. HipH localizes on nucleoid and functions as a potent DNase, inducing cells into a viable but non-culturable state. Conversely, c-di-GMP interacts with HipH, reducing its genotoxic effects and enabling cells to enter a persister state, resulting in drug tolerance. Importantly, by targeting this toxin-antitoxin system, we repressed drug tolerance in Uropathogenic Escherichia coli infections, offering promising therapeutic strategies against chronic and relapsing infections.
2024-02-20 | GSE239503 | GEO