Non-lethal exposure to H<sub>2</sub>O<sub>2</sub> boosts bacterial survival and evolvability against oxidative stress

Rodríguez‐Rojas, Alexandro; Kim, Josh Jay; Johnston, Paul R.; Makarova, Olga; Eravci, Murat; Weise, Christoph; Hengge, Regine; Rolff, Jens

doi:10.1101/575134

Cited by 5 publications

(5 citation statements)

References 81 publications

(100 reference statements)

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“…This is consistent with the expectation that the mismatch rate scales with the replication rate (Rosche & Foster, 2000;Robert et al, 2018). Our observation that the mutagenesis burst also occurs at H 2 O 2 concentrations that inhibit growth completely (> 200 μM in microfluidic culture, Fig EV2 ) indicates that it may contribute to the acquisition of mutations that enable evolutionary rescue during lethal stress (Rodriguez-Rojas et al, 2020).…”

Section: Sudden Oxidative Stress Causes a Burst Of Mutationssupporting

confidence: 90%

“…We generated a strain with a constitutive OxyR response by elevating endogenous H 2 O 2 levels with a deletion of the alkyl hydroperoxidase gene ahpC (Seaver & Imlay, 2001a). This strain showed increased basal expression of the PgrxA reporter before treatment (Fig Exposing cells to sublethal concentrations of H 2 O 2 is known to increase their survival of subsequent treatments (Imlay, 2008;Rodriguez-Rojas et al, 2020). To test whether priming adaptation can also protect against the mutagenesis burst, we pretreated cells with a low dose of H 2 O 2 (25 μM) for 4 h before exposure to the higher dose (100 μM).…”

Section: Constitutive Oxyr Response and Priming Adaptation Prevent Th...mentioning

confidence: 99%

“…The mutagenic effects of ROS are thought to accelerate the evolution of antibiotic resistance and host adaptation (Weitzman & Stossel, 1981;Kohanski et al, 2010a;Long et al, 2016;Wang et al, 2018). Interestingly, the mutation supply driving such genetic adaptation was shown to depend on the temporal pattern of ROS exposure (Rodriguez-Rojas et al, 2020), suggesting that mutation rates may be dynamically modulated by changes in the stress level and the cellular stress responses.…”

Section: Introductionmentioning

confidence: 99%

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Adaptation delay causes a burst of mutations in bacteria responding to oxidative stress

2022

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Understanding the interplay between phenotypic and genetic adaptation is a focus of evolutionary biology. In bacteria, the oxidative stress response prevents mutagenesis by reactive oxygen species (ROS). We hypothesise that the stress response dynamics can therefore affect the timing of the mutation supply that fuels genetic adaptation to oxidative stress. We uncover that sudden hydrogen peroxide stress causes a burst of mutations. By developing single‐molecule and single‐cell microscopy methods, we determine how these mutation dynamics arise from phenotypic adaptation mechanisms. H2O2 signalling by the transcription factor OxyR rapidly induces ROS‐scavenging enzymes. However, an adaptation delay leaves cells vulnerable to the mutagenic and toxic effects of hydroxyl radicals generated by the Fenton reaction. Resulting DNA damage is counteracted by a spike in DNA repair activities during the adaptation delay. Absence of a mutation burst in cells with prior stress exposure or constitutive OxyR activation shows that the timing of phenotypic adaptation directly controls stress‐induced mutagenesis. Similar observations for alkylation stress show that mutation bursts are a general phenomenon associated with adaptation delays.

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Section: Sudden Oxidative Stress Causes a Burst Of Mutationssupporting

confidence: 90%

Section: Constitutive Oxyr Response and Priming Adaptation Prevent Th...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adaptation delay causes a burst of mutations in bacteria responding to oxidative stress

2022

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“…Therefore, rather than being exposed suddenly, barrier cells are able to adapt to a gradual increase in H2O2 concentration. Such gradual adaptation is known to enhance survival of higher stress levels (Imlay, 2008;Lagage et al, 2022;Rodríguez-Rojas et al, 2020). To confirm this "priming" effect underlies the high stress tolerance of the barrier cells, we applied a gradual increase of H2O2 concentration reaching up to 500 µM over 18 minutes [Figure 5A], which greatly increased the fraction of cells that recovered growth after H2O2 removal, compared to sudden treatment with 500 µM H2O2 [Figure 5B].…”

Section: Barrier Cells Obtain High H2o2 Tolerance Via Gradual Adaptationmentioning

confidence: 98%

Environmental feedback drives oxidative stress response heterogeneity in bacterial populations

Choudhary

Lagage

Foster

et al. 2022

Preprint

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Induction of phenotypic heterogeneity is a ubiquitous consequence of bacterial stress responses. It is commonly postulated that isogenic cells exploit stochastic molecular fluctuations to generate phenotypic heterogeneity as a population survival strategy (termed bet-hedging). However, it is also possible that each cell attempts to maximise its own chances of survival. In that case, the apparent heterogeneity could either be caused by inevitable molecular noise or by underlying deterministic mechanisms which have escaped observation. Here, we investigated the sources and consequences of gene expression heterogeneity in the response of Escherichia coli cells to hydrogen peroxide (H2O2) stress. A machine-learning model accurately predicted the variable responses of individual cells growing in structured populations, indicating that the phenotypic heterogeneity has a deterministic origin. The model further showed that spatio-temporal dynamics in H2O2 concentration were dictated by the H2O2 scavenging capacity and morphology of cells in the local environment. Hence, oxidative stress response fluctuations were in fact the result of a precise and rapid feedback between each cell and its immediate environment. Although single cells optimise their individual responses, the formation of short-range H2O2 gradients by their scavenging activities increases stress tolerance at the population level and leads to spatial variation in mutation rates.

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“…Since there is modest death at this early time point (Fig 3G at 1.5h), we assumed if ROS is involved it would be within the range of the lowest concentrations for mode one killing, which is due to DNA damage: 1 to 3 mM H2O2 [53]. We tested the lowest concentration within this range as in [54]. A significant elevation in ROS was observed for these samples (S7 Fig).…”

Section: Consistent Genetic and Transcriptional Evidence For The Role...mentioning

confidence: 99%

Intracellular acidification is a hallmark of thymineless death in E. coli

Ketcham

Freddolino

Tavazoie

2022

Preprint

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Thymidine starvation causes rapid cell death. This enigmatic process known as thymineless death (TLD) is the underlying killing mechanism of diverse antimicrobial and antineoplastic drugs. Despite decades of investigation, we still lack a mechanistic understanding of the causal sequence of events that culminate in TLD. Here, we used a diverse set of unbiased approaches to systematically determine the genetic and regulatory underpinnings of TLD in Escherichia coli. In addition to discovering novel genes in previously implicated pathways, our studies revealed a critical and previously unknown role for intracellular acidification in TLD. We observed that a decrease in cytoplasmic pH is a robust early event in TLD across diverse genetic backgrounds. Furthermore, we show that acidification is a causal event in the death process, as chemical and genetic perturbations that increase intracellular pH substantially reduce killing. We also observe a decrease in intracellular pH in response to exposure to the antibiotic gentamicin, suggesting that intracellular acidification may be a common mechanistic step in the bactericidal effects of other antibiotics.

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Non-lethal exposure to H₂O₂ boosts bacterial survival and evolvability against oxidative stress

Cited by 5 publications

References 81 publications

Adaptation delay causes a burst of mutations in bacteria responding to oxidative stress

Adaptation delay causes a burst of mutations in bacteria responding to oxidative stress

Environmental feedback drives oxidative stress response heterogeneity in bacterial populations

Intracellular acidification is a hallmark of thymineless death in E. coli

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Non-lethal exposure to H2O2 boosts bacterial survival and evolvability against oxidative stress

Cited by 5 publications

References 81 publications

Adaptation delay causes a burst of mutations in bacteria responding to oxidative stress

Adaptation delay causes a burst of mutations in bacteria responding to oxidative stress

Environmental feedback drives oxidative stress response heterogeneity in bacterial populations

Intracellular acidification is a hallmark of thymineless death in E. coli

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Product

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Non-lethal exposure to H₂O₂ boosts bacterial survival and evolvability against oxidative stress