scholarly journals PixR, a novel activator of conjugative transfer of IncX4 resistance plasmids, mitigates the fitness cost of mcr-1 carriage in Escherichia coli

2021 ◽  
Author(s):  
Lingxian Yi ◽  
Romain Durand ◽  
Frédéric Grenier ◽  
Jun Yang ◽  
Kaiyang Yu ◽  
...  
Keyword(s):  
Transcriptional Regulator ◽  
Fitness Cost ◽  
Host Bacterium ◽  
Regulator Gene ◽  
Rna Seq ◽  
Colistin Resistance ◽  
Bacterial Populations ◽  
Transfer Genes ◽  
Resistance Plasmids ◽  
Competition Assays

The emergence of the plasmid-borne colistin resistance gene mcr-1 threats public health. IncX4-type plasmids are one of the most epidemiologically successful vehicles for spreading mcr-1 worldwide. Since MCR-1 is known for imposing a fitness cost to its host bacterium, the successful spread of mcr-1-bearing plasmids might be linked to high conjugation frequency, which would enhance the maintenance of the plasmid in the host without antibiotic selection. However, the mechanism of IncX4 plasmids conjugation remains unclear. In this study, we used high-density transposon mutagenesis to identify factors required for IncX4 plasmid transfer and 18 genes were identified, including five with annotations unrelated to conjugation. The Cappable-seq and RNA-seq analysis confirmed that a novel transcriptional regulator gene, pixR, directly regulates the transfer of IncX4 plasmids by binding the promoter of 13 essential transfer genes to increase their transcription. Plasmid invasion and co-culture competition assays revealed that pixR is essential for the spread and persistence of mcr-1>-bearing IncX4 plasmids in bacterial populations, and effective conjugation is crucial for alleviating the fitness cost exerted by mcr-1 carriage. The existence of the IncX4-specific pixR gene increases plasmid transmissibility while promoting the invasion and persistence of mcr-1-bearing plasmids in bacterial populations, which helps explain their global prevalence.

scholarly journals Compensatory mutations modulate the competitiveness and dynamics of plasmid-mediated colistin resistance in Escherichia coli clones

2020 ◽  
Vol 14 (3) ◽  
pp. 861-865 ◽  
Author(s):  
Qiu E. Yang ◽  
Craig MacLean ◽  
Andrei Papkou ◽  
Manon Pritchard ◽  
Lydia Powell ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Fitness Landscape ◽  
Fitness Cost ◽  
Colistin Resistance ◽  
Bacterial Populations ◽  
Compensatory Evolution ◽  
Neutral Mutations ◽  
The Cost ◽  
Negative Epistasis

AbstractThe emergence of mobile colistin resistance (mcr) threatens to undermine the clinical efficacy of the last antibiotic that can be used to treat serious infections caused by Gram-negative pathogens. Here we measure the fitness cost of a newly discovered MCR-3 using in vitro growth and competition assays. mcr-3 expression confers a lower fitness cost than mcr-1, as determined by competitive ability and cell viability. Consistent with these findings, plasmids carrying mcr-3 have higher stability than mcr-1 plasmids across a range of Escherichia coli strains. Crucially, mcr-3 plasmids can stably persist, even in the absence of colistin. Recent compensatory evolution has helped to offset the cost of mcr-3 expression, as demonstrated by the high fitness of mcr-3.5 as opposed to mcr-3.1. Reconstructing all of the possible evolutionary trajectories from mcr-3.1 to mcr-3.5 reveals a complex fitness landscape shaped by negative epistasis between compensatory and neutral mutations. Our findings highlight the importance of fitness costs and compensatory evolution in driving the dynamics and stability of mobile colistin resistance in bacterial populations, and they highlight the need to understand how processes (other than colistin use) impact mcr dynamics.

Transcriptional regulation of cytoskeletal functions and segmentation by a novel maternal pair-rule gene, lilliputian

Development ◽  
2001 ◽  
Vol 128 (5) ◽  
pp. 801-813 ◽  
Author(s):  
A.H. Tang ◽  
T.P. Neufeld ◽  
G.M. Rubin ◽  
H.A. Muller
Keyword(s):  
Transcriptional Control ◽  
Fragile X ◽  
Transcriptional Regulator ◽  
Regulator Gene ◽  
Embryonic Patterning ◽  
Fushi Tarazu ◽  
Fragile X Mental Retardation ◽  
Pair Rule Gene ◽  
Mutant Phenotypes ◽  
Pair Rule

Transcriptional control during early Drosophila development is governed by maternal and zygotic factors. We have identified a novel maternal transcriptional regulator gene, lilliputian (lilli), which contains an HMG1 (AT-hook) motif and a domain with similarity to the human fragile X mental retardation FMR2 protein and the AF4 proto-oncoprotein. Embryos lacking maternal lilli expression show specific defects in the establishment of a functional cytoskeleton during cellularization, and exhibit a pair-rule segmentation phenotype. These mutant phenotypes correlate with markedly reduced expression of the early zygotic genes serendipity alpha, fushi tarazu and huckebein, which are essential for cellularization and embryonic patterning. In addition, loss of lilli in adult photoreceptor and bristle cells results in a significant decrease in cell size. Our results indicate that lilli represents a novel pair-rule gene that acts in cytoskeleton regulation, segmentation and morphogenesis.

scholarly journals Stochastic bacterial population dynamics restrict the establishment of antibiotic resistance from single cells

2020 ◽  
Vol 117 (32) ◽  
pp. 19455-19464 ◽  
Author(s):  
Helen K. Alexander ◽  
R. Craig MacLean
Keyword(s):  
De Novo ◽  
Single Cells ◽  
Treatment Strategies ◽  
Bacterial Populations ◽  
Resistance Plasmids ◽  
Evolution Of Resistance ◽  
Resistant Strains ◽  
Low Probability ◽  
Emergence Of Resistance ◽  
Resistant Cells

A better understanding of how antibiotic exposure impacts the evolution of resistance in bacterial populations is crucial for designing more sustainable treatment strategies. The conventional approach to this question is to measure the range of concentrations over which resistant strain(s) are selectively favored over a sensitive strain. Here, we instead investigate how antibiotic concentration impacts the initial establishment of resistance from single cells, mimicking the clonal expansion of a resistant lineage following mutation or horizontal gene transfer. Using twoPseudomonas aeruginosastrains carrying resistance plasmids, we show that single resistant cells have <5% probability of detectable outgrowth at antibiotic concentrations as low as one-eighth of the resistant strain’s minimum inhibitory concentration (MIC). This low probability of establishment is due to detrimental effects of antibiotics on resistant cells, coupled with the inherently stochastic nature of cell division and death on the single-cell level, which leads to loss of many nascent resistant lineages. Our findings suggest that moderate doses of antibiotics, well below the MIC of resistant strains, may effectively restrict de novo emergence of resistance even though they cannot clear already-large resistant populations.

scholarly journals Activation of PLAG1 and HMGA2 by gene fusions involving the transcriptional regulator gene NFIB

2020 ◽  
Vol 59 (11) ◽  
pp. 652-660 ◽  
Author(s):  
Maryam Kakay Afshari ◽  
André Fehr ◽  
Paloma Tejera Nevado ◽  
Mattias K. Andersson ◽  
Göran Stenman
Keyword(s):  
Transcriptional Regulator ◽  
Gene Fusions ◽  
Regulator Gene

scholarly journals Identification of KLF6/PSGs and NPY-Related USF2/CEACAM Transcriptional Regulatory Networks via Spinal Cord Bulk and Single-Cell RNA-Seq Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Xinbing Liu ◽  
Wei Gao ◽  
Wei Liu
Keyword(s):  
Spinal Cord ◽  
Single Cell ◽  
Regulatory Networks ◽  
Single Cell Analysis ◽  
Transcriptional Regulatory Network ◽  
Transcriptional Regulator ◽  
Cell Analysis ◽  
Rna Seq ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory

Background. To further understand the development of the spinal cord, an exploration of the patterns and transcriptional features of spinal cord development in newborn mice at the cellular transcriptome level was carried out. Methods. The mouse single-cell sequencing (scRNA-seq) dataset was downloaded from the GSE108788 dataset. Single-cell RNA-Seq (scRNA-Seq) was conducted on cervical and lumbar spinal V2a interneurons from 2 P0 neonates. Single-cell analysis using the Seurat package was completed, and marker mRNAs were identified for each cluster. Then, pseudotemporal analysis was used to analyze the transcription changes of marker mRNAs in different clusters over time. Finally, the functions of these marker mRNAs were assessed by enrichment analysis and protein-protein interaction (PPI) networks. A transcriptional regulatory network was then constructed using the TRRUST dataset. Results. A total of 949 cells were screened. Single-cell analysis was conducted based on marker mRNAs of each cluster, which revealed the heterogeneity of neonatal mouse spinal cord neuronal cells. Functional analysis of pseudotemporal trajectory-related marker mRNAs suggested that pregnancy-specific glycoproteins (PSGs) and carcinoembryonic antigen cell adhesion molecules (CEACAMs) were the core mRNAs in cluster 3. GSVA analysis then demonstrated that the different clusters had differences in pathway activity. By constructing a transcriptional regulatory network, USF2 was identified to be a transcriptional regulator of CEACAM1 and CEACAM5, while KLF6 was identified to be a transcriptional regulator of PSG3 and PSG5. This conclusion was then validated using the Genotype-Tissue Expression (GTEx) spinal cord transcriptome dataset. Conclusions. This study completed an integrated analysis of a single-cell dataset with the utilization of marker mRNAs. USF2/CEACAM1&5 and KLF6/PSG3&5 transcriptional regulatory networks were identified by spinal cord single-cell analysis.

scholarly journals PixR, a Novel Activator of Conjugative Transfer of IncX4 Resistance Plasmids, Mitigates the Fitness Cost of mcr-1 Carriage in Escherichia coli

mBio ◽  
2022 ◽  
Author(s):  
Lingxian Yi ◽  
Romain Durand ◽  
Frédéric Grenier ◽  
Jun Yang ◽  
Kaiyang Yu ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Molecular Mechanisms ◽  
Antibiotic Resistance Genes ◽  
Fitness Cost ◽  
Conjugative Transfer ◽  
Resistance Plasmids

The spread of clinically relevant antibiotic resistance genes is often linked to the dissemination of epidemic plasmids. However, the underlying molecular mechanisms contributing to the successful spread of epidemic plasmids remain unclear.

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