Effect of fluoroquinolone-induced gyrase cleavage sites on gene expression during drug treatment period and recovery period on E. coli
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PROVIDER: PRJNA851455 | ENA |
REPOSITORIES: ENA
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Project description:Fluoroquinolone-induced gyrase cleavage sites
| PRJNA851452 | ENA
Project description: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.
2022-12-05 | GSE206609 | GEO
Project description: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.
2022-12-05 | GSE206608 | GEO
Project description:Genome-wide mapping of fluoroquinolone-induced gyrase cleavage sites displays drug specific effects that correlate with bacterial persistence
| PRJNA851453 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-12-05 | GSE206610 | GEO
Project description:The design of novel antibiotics that break antimicrobial resistance relies on a profound understanding of their mechanism of action. While it has been shown that the cellular effects of antibiotics cluster according to their molecular targets, we investigated whether compounds binding to different sites of the same target can be differentiated by their transcriptome or metabolome signatures. The effects of three fluoroquinolones, two aminocoumarins and two cystobactamids, all inhibiting bacterial gyrase, on Pseudomonas aeruginosa at sub-inhibitory concentrations were captured by RNA sequencing.
2021-05-03 | GSE166602 | GEO
Project description:Targeting bacterial gyrase with cystobactamid, fluoroquinolone and aminocoumarin antibiotics induces distinct molecular signatures in Pseudomonas aeruginosa
| PRJNA701395 | ENA
Project description:DNA gyrase is an essential enzyme whose activity is required for DNA replication and chromosome maintenance. Inhibition of gyrase results in multiple physiological effects including changes in DNA superhelicity, replication arrest and DNA damage. Using genetic, genomic, statistical and biochemical techniques, we have untangled the contribution of individual effects, assessed their relative significance and concluded that: i) DNA replication is required for the formation of spatial transcriptional domains; ii) transcriptional response to gyrase inhibition is coordinated between at least two modules involved in DNA maintenance, relaxation and damage response; iii) genes whose transcriptional response to gyrase inhibition does not depend on the activity of topoisomerase I can be classified on the basis of the GC excess in their upstream and coding sequences into, respectively, activated and repressed by gyrase inhibition; iv) relaxation by topoisomerase I dominates the transcriptional response upon gyrase inhibition, followed by the effects of replication and RecA. Keywords: time course
2006-03-10 | GSE4408 | GEO
Project description:Various bis-benzimidazole derivatives have been reported to possess activity against Gram-positive pathogens. No mechanism of action has been elucidated to fully account for the antibacterial activity of this class of compounds. A group of symmetric bis-benzimidazoles (BBZ) designed as anticancer agents have previously been shown to possess moderate antiproliferative activity. We sought to assess the antibacterial activity and mechanism of action of BBZ compounds against Staphylococcus aureus. Antibacterial activities were assessed by determination of minimal inhibitory concentrations (MICs), time-kill curves, and scanning electron microscopy. Transcriptional responses to BBZ treatment were determined using whole genome microarrays. Activities against bacterial type II topoisomerases were investigated using in vitro supercoiling, decatenation, DNA binding, and DNA cleavage inhibition assays. MICs for EMRSA-16 were between 0.03 and 0.5 μg/mL. The compounds showed concentration-dependent bactericidal activity and induced cell swelling and lysis. Transcriptional responses to BBZ were consistent with topoisomerase inhibition and DNA damage. A subset of BBZ compounds inhibited S. aureus DNA gyrase supercoiling activity with IC50 values in the range of 5−10 μM. This inhibition was subsequently shown to operate through both inhibition of binding of DNA gyrase to DNA and accumulation of single-stranded DNA breaks. We conclude that BBZ compounds are potent antistaphylococcal agents and operate at least in part through DNA gyrase inhibition, leading to the accumulation of single-stranded DNA breaks, and by preventing the binding of gyrase to DNA. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-106]
2012-10-14 | E-BUGS-106 | biostudies-arrayexpress
Project description:Type II topoisomerases (topos) are a ubiquitous and essential class of enzymes that form transient enzyme-bound double-stranded breaks on DNA called cleavage complexes. The location and frequency of these cleavage complexes on DNA is important for cellular function, genomic stability, and a number of clinically important anticancer and antibacterial drugs, e.g., quinolones. We developed a simple high-accuracy end-sequencing (SHAN-seq) method to sensitively map type II topo cleavage complexes on DNA in vitro. Using SHAN-seq, we detected Escherichia coli gyrase and topoisomerase IV cleavage complexes at hundreds of sites on supercoiled pBR322 DNA, approximately one site every ten bp, with frequencies that varied by two-to-three orders of magnitude. These sites included previously identified sites and 20-50 fold more new sites. We show that the location and frequency of cleavage complexes at these sites are enzyme-specific and vary substantially in the presence of the quinolone, ciprofloxacin, but not with DNA supercoil chirality, i.e., negative vs. positive supercoiling. SHAN-seq’s exquisite sensitivity provides an unprecedented single-nucleotide resolution view of the distribution of gyrase and topoisomerase IV cleavage complexes on DNA. Moreover, the discovery that these enzymes can cleave DNA at orders of magnitude more sites than the relatively few previously known sites resolves the apparent paradox of how these enzymes resolve topological problems throughout the genome.
2024-08-06 | GSE267149 | GEO