Landscapes of collateral fitness effects of mutations in antibiotic resistance genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA819053 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18454757_1.fastq.gz | Fastqsanger.gz | |||
| SRR18454757_2.fastq.gz | Fastqsanger.gz | |||
| SRR18454758_1.fastq.gz | Fastqsanger.gz | |||
| SRR18454758_2.fastq.gz | Fastqsanger.gz | |||
| SRR18454759_1.fastq.gz | Fastqsanger.gz |
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Project description:Collateral fitness effects of mutations
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Project description:We performed RNA-seq experiments to compare the gene expression profiles of cells expressing single-codon substitutions in the antibiotic resistance genes NDM-1, CAT-I, or aadB in the absence of antibiotics. Mutations with deleterious fitness effects in the absense of antibiotics also caused significant changes in gene expression in a number of genes related to stress-response pathways including the regulator of colanic acid capsule synthesis (Rcs) response, the phage shock protein response (Psp), and the oxidative stress response. Fold differences in gene expression were mutation- and gene-dependent.
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Project description:Cationic antimicrobial peptides (CAPs) are promising novel alternatives to conventional antibacterial agents, but the overlap in resistance mechanisms between small-molecule antibiotics and CAPs is unknown. Does evolution of antibiotic resistance decrease (cross-resistance) or increase (collateral sensitivity) susceptibility to CAPs? We systematically addressed this issue by studying the susceptibilities of a comprehensive set of antibiotic resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic resistant bacteria frequently showed collateral sensitivity to CAPs, while cross-resistance was relatively rare. We identified clinically relevant multidrug resistance mutations that simultaneously elevate susceptibility to certain CAPs. Transcriptome and chemogenomic analysis revealed that such mutations frequently alter the lipopolysaccharide composition of the outer cell membrane and thereby increase the killing efficiency of membrane-interacting antimicrobial peptides. Furthermore, we identified CAP-antibiotic combinations that rescue the activity of existing antibiotics and slow down the evolution of resistance to antibiotics. Our work provides a proof of principle for the development of peptide based antibiotic adjuvants that enhance antibiotic action and block evolution of resistance.
2018-03-29 | GSE96706 | GEO
Project description:We performed RNA-seq experiments to compare the gene expression profiles of cells expressing TEM-1 beta-lactamase with single-codon substitutions in the absence of beta-lactam antibiotics. Mutations with deleterious fitness effects in the absense of antibiotics also caused significant changes in gene expression, primarily in the induction of specific outer envelope stress response pathways and, in some cases, the mild-induction of a few genes in the heat-shock response pathway.
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Project description:Landscapes of collateral fitness effects of mutations in antibiotic resistance genes
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Project description:In adaptive evolution, an increase in fitness to an environment is frequently accompanied by changes in fitness to other environmental conditions, called cross-resistance and sensitivity. Although the networks between fitness changes affect the course of evolution substantially, the mechanisms underlying such fitness changes are yet to be fully elucidated. Herein, we performed high-throughput laboratory evolution of Escherichia coli under various stress conditions using an automated culture system, and quantified how the acquisition of resistance to one stressor alters the resistance to other stressors. We demonstrated that resistance changes could be quantitatively predicted based on changes in the transcriptome of the resistant strains. We also identified several genes and gene functions, for which mutations were commonly fixed in the strains resistant to the same stress, which could partially explain the observed cross-resistance and collateral sensitivity. The integration of transcriptome and genome data enabled us to clarify the bacterial stress resistance mechanisms.
2017-10-17 | GSE89746 | GEO
Project description:Synonymous mutations do not change the sequence of the polypeptide but they may still influence fitness. We investigated in Salmonella enterica how four synonymous mutations in the rpsT gene (encoding ribosomal protein S20) reduce fitness (i.e. growth rate) and the mechanisms by which this cost can be genetically compensated. The reduced growth rates of the synonymous mutants were correlated with reduced levels of the rpsT transcript and S20 protein. In an adaptive evolution experiment these fitness impairments could be compensated by mutations that either caused up-regulation of S20 through increased gene dosage (due to duplications), increased transcription of the rpsT gene (due to an rpoD mutation or mutations in rpsT), or increased translation from the rpsT transcript (due to rpsT mutations). We suggest that the reduced levels of S20 in the synonymous mutants result in production of a defective subpopulation of 30S subunits lacking S20 that reduce protein synthesis and bacterial growth and that the compensatory mutations restore S20 levels and the number of functional ribosomes. Our results demonstrate how specific synonymous mutations can cause substantial fitness reductions and that many different types intra- and extragenic compensatory mutations can efficiently restore fitness. Furthermore, our study highlights that also synonymous sites can be under strong selection, which may have implications for the use of dN/dS ratios as signature for selection.
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Project description:Multi-environment fitness landscapes of a tRNA gene
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Project description:Bacteria in biofilms have higher antibiotic tolerance than their planktonic counterparts. A major outstanding question is the degree to which the biofilm-specific cellular state and its constituent genetic determinants contribute to this hyper-tolerant phenotype. Here, using genome-wide functional profiling of a complex, heterogeneous mutant population of Pseudomonas aeruginosa MPAO1, we identified large sets of mutations that contribute to antibiotic tolerance predominantly in the biofilm or planktonic setting only. Our mixed population-based experimental design recapitulated the complexity of natural biofilms and, unlike previous studies, revealed clinically observed behaviors including the emergence of quorum sensing-deficient mutants. Our study revealed a substantial contribution of the cellular state to the antibiotic tolerance of biofilms, providing a rational foundation for the development of novel therapeutics against P. aeruginosa biofilm-associated infections. This dataset compares the expression of SAH108, a strain with enhanced antibiotic tolerance in the biofilm state, to expression in wild-type strains. We compared the expression of two biological replicates from strain SAH108 to samples from three wild-type, reference strains. All samples were collected from exponentially-growing planktonic cultures.
2011-11-21 | E-GEOD-26142 | biostudies-arrayexpress
Project description:Mutations in the rifampicin (Rif)-binding site of RNA polymerase (RNAP) impart antibiotic resistance and inextricably affect transcription initiation, elongation, and termination properties as well. At each step of the transcription cycle, RNAP responds to non-essential transcription factors, signaling molecules, and substrate availability. As such, the non- essential genome and its impact on fitness cost potentially represent an untapped resource for new combination therapies. Using transposon sequencing (Tn-seq), we present a genome- wide analysis of resistance cost in a clinically common rpoB H526Y mutant. Our data show that cost-compounding genes include factors that promote high transcription elongation rate, whereas cost-mitigating genes function in cell wall synthesis and division. We demonstrate that cell wall synthesis and division defects in rpoB H526Y are a consequence of an abnormally high transcription elongation rate, which is further exacerbated by superfluous activity of the uracil salvage pathway and indifference of the mutant RNAP to alarmone ppGpp. Leveraging on this knowledge, we identified drugs that are highly potent against rpoB H526Y and other RifR alleles from the same phenotypic class. Thus, genome-wide analysis of fitness cost of antibiotic resistant mutants should expedite discovery of new combination therapies and delineate cellular pathways that underlie molecular mechanisms of cost.
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