Topoisomerase IV tracks behind the replication fork and the SeqA complex during DNA replication in Escherichia coli

Helgesen, Emily; Sætre, Frank; Skarstad, Kirsten

doi:10.1038/s41598-020-80043-4

Cited by 19 publications

(13 citation statements)

References 41 publications

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“…S14). Notably, parC was enriched in mutations yet to a lesser degree (only 5 variants in 3 families) than its close homolog gyrA, possibly because of reduced selective pressure due to its distinct role compared to DNA gyrase 53 , and in contrast to previous findings suggesting that Gram positive bacteria evolve primarily through mutations in parC 28 . Other implicated KOs included efflux pumps (K02004), DNA helicases (K02314, K03657), transport systems (K01537, K02051, K11085), transcription factors (K19505) and phage-associated genes (K01421).…”

Section: Convergent Evolution Focused On Gyracontrasting

confidence: 60%

A short course of antibiotics selects for persistent resistance in the human gut

Yaffe,

Dethlefsen,

Patankar

et al. 2023

Preprint

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Understanding the relationship between antibiotic use and the evolution of antimicrobial resistance is vital for effective antibiotic stewardship, yet animal models and in vitro experiments poorly replicate real-world conditions. To elucidate how resistance evolves in vivo, we exposed 60 human subjects to ciprofloxacin and used longitudinal stool samples and a new computational method to assemble genomes for 5665 populations of commensal bacterial species within subjects. Analysis of 2.27M polymorphic sequence variants revealed 513 populations that underwent selective sweeps. We found convergent evolution focused on DNA gyrase and evidence of dispersed selective pressure at other genomic loci. Nearly 10% of susceptible bacterial populations evolved towards resistance through sweeps that involved mutations in a specific amino acid in gyrase. Evolution towards resistance was predicted by population abundances before and during the exposure. 89% of gyrase sweeps and the majority of all sweeps persisted more than 10 weeks. This work quantifies the direct relationship between antibiotic usage and the evolution of resistance within the gut communities of individual human hosts.

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Section: Convergent Evolution Focused On Gyracontrasting

confidence: 60%

A short course of antibiotics selects for persistent resistance in the human gut

Yaffe,

Dethlefsen,

Patankar

et al. 2023

Preprint

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“…SeqA binds hemimethylated DNA and therefore effectively follows the replisome during replication. It is required for temporary cohesion of newly replicated regions, which may be achieved by inhibition of Topo IV activity on SeqA-bound hemimethylated chromosomal regions behind the replisome ( Joshi et al, 2013 ; Helgesen et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Single-nucleotide resolution detection of Topo IV cleavage activity in the Escherichia coli genome with Topo-Seq

et al. 2023

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Topoisomerase IV (Topo IV) is the main decatenation enzyme in Escherichia coli; it removes catenation links that are formed during DNA replication. Topo IV binding and cleavage sites were previously identified in the E. coli genome with ChIP-Seq and NorfIP. Here, we used a more sensitive, single-nucleotide resolution Topo-Seq procedure to identify Topo IV cleavage sites (TCSs) genome-wide. We detected thousands of TCSs scattered in the bacterial genome. The determined cleavage motif of Topo IV contained previously known cleavage determinants (−4G/+8C, −2A/+6 T, −1 T/+5A) and additional, not observed previously, positions −7C/+11G and −6C/+10G. TCSs were depleted in the Ter macrodomain except for two exceptionally strong non-canonical cleavage sites located in 33 and 38 bp from the XerC-box of the dif-site. Topo IV cleavage activity was increased in Left and Right macrodomains flanking the Ter macrodomain and was especially high in the 50–60 kb region containing the oriC origin of replication. Topo IV enrichment was also increased downstream of highly active transcription units, indicating that the enzyme is involved in relaxation of transcription-induced positive supercoiling.

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“…Together these enzymes work to relieve the enormous torsional stress and topological constraints present during DNA replication. Inhibition of these enzymes results in DNA shearing preventing replication [60,61]. Resistance to fluoroquinolones in S. aureus occurs through two main mechanisms.…”

Section: Nucleic Acid Biosynthesismentioning

confidence: 99%

Staph wars: the antibiotic pipeline strikes back

Douglas,

Laabei

2023

Microbiology

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Antibiotic chemotherapy is widely regarded as one of the most significant medical advancements in history. However, the continued misuse of antibiotics has contributed to the rapid rise of antimicrobial resistance (AMR) globally. Staphylococcus aureus , a major human pathogen, has become synonymous with multidrug resistance and is a leading antimicrobial-resistant pathogen causing significant morbidity and mortality worldwide. This review focuses on (1) the targets of current anti-staphylococcal antibiotics and the specific mechanisms that confirm resistance; (2) an in-depth analysis of recently licensed antibiotics approved for the treatment of S. aureus infections; and (3) an examination of the pre-clinical pipeline of anti-staphylococcal compounds. In addition, we examine the molecular mechanism of action of novel antimicrobials and derivatives of existing classes of antibiotics, collate data on the emergence of resistance to new compounds and provide an overview of key data from clinical trials evaluating anti-staphylococcal compounds. We present several successful cases in the development of alternative forms of existing antibiotics that have activity against multidrug-resistant S. aureus . Pre-clinical antimicrobials show promise, but more focus and funding are required to develop novel classes of compounds that can curtail the spread of and sustainably control antimicrobial-resistant S. aureus infections.

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Topoisomerase IV tracks behind the replication fork and the SeqA complex during DNA replication in Escherichia coli

Cited by 19 publications

References 41 publications

A short course of antibiotics selects for persistent resistance in the human gut

A short course of antibiotics selects for persistent resistance in the human gut

Single-nucleotide resolution detection of Topo IV cleavage activity in the Escherichia coli genome with Topo-Seq

Staph wars: the antibiotic pipeline strikes back

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