Digital Insights Into Nucleotide Metabolism and Antibiotic Treatment Failure

Lopatkin, Allison J.; Yang, Jason H.

doi:10.3389/fdgth.2021.583468

Cited by 26 publications

(17 citation statements)

References 87 publications

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“…Both lineages up-regulated the flhDC regulator LrhA at the premutation stage, hinting that down-regulation of the flagellar biosynthetic cascade is a shared trait in the early stages of adaptation to a sodium-poor environment. Similarly, both lineages up-regulated nucleotide catabolic processes and salvage pathways, a feature also observed in antibiotic response, and which can affect mutation rates by disturbing the nucleotide triphosphate balance in the cellular pool (38)(39)(40). This might suggest that the mutations were a product of stress-induced mutagenesis, a known facilitator of evolution (41), which has been proposed to involve RpoS-mediated up-regulation of the DinB error-prone polymerase (42).…”

Section: Discussionmentioning

confidence: 93%

The rapid evolution of flagellar ion selectivity in experimental populations of E. coli

et al. 2022

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Determining which cellular processes facilitate adaptation requires a tractable experimental model where an environmental cue can generate variants that rescue function. The bacterial flagellar motor (BFM) is an excellent candidate—an ancient and highly conserved molecular complex for bacterial propulsion toward favorable environments. Motor rotation is often powered by H + or Na + ion transit through the torque-generating stator subunit of the motor complex, and ion selectivity has adapted over evolutionary time scales. Here, we used CRISPR engineering to replace the native Escherichia coli H + -powered stator with Na + -powered stator genes and report the spontaneous reversion of our edit in a low-sodium environment. We followed the evolution of the stators during their reversion to H + -powered motility and used both whole-genome and RNA sequencing to identify genes involved in the cell’s adaptation. Our transplant of an unfit protein and the cells’ rapid response to this edit demonstrate the adaptability of the stator subunit and highlight the hierarchical modularity of the flagellar motor.

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Section: Discussionmentioning

confidence: 93%

The rapid evolution of flagellar ion selectivity in experimental populations of E. coli

et al. 2022

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“…Both lineages upregulated the flhDC regulator LrhA at the premutation stage, suggesting that downregulation of the flagellar biosynthetic cascade is a shared trait contributing to stator adaptation. Similarly, both lineages upregulated nucleotide catabolic processes and salvage pathways, a feature also observed also in antibiotic response and which can affect mutation rates by disturbing the NTP balance in the cellular pool (Pang, McFaline et al 2012, Foster, Lee et al 2015, Lopatkin and Yang 2021.…”

Section: Discussionmentioning

confidence: 83%

“…Both lineages upregulated the flhDC regulator LrhA at the pre-mutation stage, hinting that downregulation of the flagellar biosynthetic cascade is a shared trait in the early stages of adaptation to a sodium-poor environment. Similarly, both lineages upregulated nucleotide catabolic processes and salvage pathways, a feature also observed in antibiotic response and which can affect mutation rates by disturbing the NTP balance in the cellular pool (37)(38)(39). This might suggest that the mutations were a product of stress-induced mutagenesis, a known facilitator of evolution (40) which has been proposed to involve RpoS-mediated upregulation of the DinB error-prone polymerase (41).…”

Section: Discussionmentioning

confidence: 94%

The rapid evolution of flagellar ion-selectivity in experimental populations ofE. coli

Ridone

Sowa

Baker

2021

Preprint

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Motility provides a selective advantage to many bacterial species and is often achieved by rotation of flagella that propel the cell towards more favourable conditions. In most species, the rotation of the flagellum, driven by the Bacterial Flagellar Motor (BFM), is powered by H+ or Na+ ion transit through the torque-generating stator subunit of the motor complex. The ionic requirements for motility appear to have adapted to environmental changes throughout history but the molecular basis of this adaptation, and the constraints which govern the evolution of the stator proteins are unknown. Here we use CRISPR-mediated genome engineering to replace the native H+-powered stator genes of E. coli with a compatible sodium-powered stator set from V. alginolyticus and subsequently direct the evolution of the stators to revert to H+-powered motility. Evidence from whole genome sequencing indicates both flagellar- and non-flagellar-associated genes that are involved in longer-term adaptation to new power sources. Overall, transplanted Na+-powered stator genes can spontaneously incorporate novel mutations that allow H+-motility when environmental Na+ is lacking.

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“…Nucleotide (purines and pyrimidines) biosynthesis pathways are suggested to be involved in antibiotic lethality. Bacterial nucleotide biosynthesis is stimulated during antibiotic treatment [64,65]. The synthesis of nucleotides for ATP storage requires more energy, followed by increasing cellular respiration, central carbon metabolism, and oxidative stress, and these metabolic disturbances eventually lead to bacterial cell death [39].…”

Section: Discussionmentioning

confidence: 99%

The Serum and Fecal Metabolomic Profiles of Growing Kittens Treated with Amoxicillin/Clavulanic Acid or Doxycycline

Stavroulaki

Suchodolski

Pilla

et al. 2022

Animals

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The long-term impact of antibiotics on the serum and fecal metabolome of kittens has not yet been investigated. Therefore, the objective of this study was to evaluate the serum and fecal metabolome of kittens with an upper respiratory tract infection (URTI) before, during, and after antibiotic treatment and compare it with that of healthy control cats. Thirty 2-month-old cats with a URTI were randomly assigned to receive either amoxicillin/clavulanic acid for 20 days or doxycycline for 28 days, and 15 cats of similar age were enrolled as controls. Fecal samples were collected on days 0, 20/28, 60, 120, and 300, while serum was collected on days 0, 20/28, and 300. Untargeted and targeted metabolomic analyses were performed on both serum and fecal samples. Seven metabolites differed significantly in antibiotic-treated cats compared to controls on day 20/28, with two differing on day 60, and two on day 120. Alterations in the pattern of serum amino acids, antioxidants, purines, and pyrimidines, as well as fecal bile acids, sterols, and fatty acids, were observed in antibiotic-treated groups that were not observed in control cats. However, the alterations caused by either amoxicillin/clavulanic acid or doxycycline of the fecal and serum metabolome were only temporary and were resolved by 10 months after their withdrawal.

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Digital Insights Into Nucleotide Metabolism and Antibiotic Treatment Failure

Cited by 26 publications

References 87 publications

The rapid evolution of flagellar ion selectivity in experimental populations of E. coli

The rapid evolution of flagellar ion selectivity in experimental populations of E. coli

The rapid evolution of flagellar ion-selectivity in experimental populations ofE. coli

The Serum and Fecal Metabolomic Profiles of Growing Kittens Treated with Amoxicillin/Clavulanic Acid or Doxycycline

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