Identifying the fitness cost of rifampicin-resistance in Mycobacterium tuberculosis through RNAseq profiling.
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB29591 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR2882380.fastq.gz | Fastqsanger.gz | |||
| ERR2882390.fastq.gz | Fastqsanger.gz | |||
| ERR2882400.fastq.gz | Fastqsanger.gz | |||
| ERR2882410.fastq.gz | Fastqsanger.gz | |||
| ERR2882420.fastq.gz | Fastqsanger.gz |
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Project description:The experiment was designed to infer the fitness cost of rifampicin-resistance in Mycobacterium tuberculosis through expression analysis. The approach relied on: 1. Tracking the expression changes occurring as a result of the rifampicin-resistance conferring mutation Ser450Leu in RpoB and subsequent gain of compensatory mutation Leu516Pro in RpoC. The hypothesis was that any cost-incurring expressional changes would be reversed in the presence of compensatory mutations. The strains in this set were described before here: PMID 22179134. 2. Comparing the impact of the same rifampicin-resistance mutation (RpoB Ser450Leu) in five different genetic backgrounds. Here the comparison was solely between RpoB Ser450Leu and their cognate drug susceptible wild type ancestor. One of the strain pairs is the same as in point 1. above.
2018-11-18 | E-MTAB-7359 | biostudies-arrayexpress
Project description:Antimicrobial resistance (AMR) poses a threat to global health and the economy. Rifampicin resistant Mycobacterium tuberculosis accounts for a third of the global AMR burden. Gaining the upper hand on AMR requires a deeper understanding of the physiology of resistance. AMR often results in the erosion of normal cell function: a fitness cost. Identifying intervention points in the mechanisms underpinning the cost of resistance in M. tuberculosis could play a pivotal role in strengthening future treatment regimens. We used a collection of M. tuberculosis strains providing an evolutionary and phylogenetic snapshot of rifampicin resistance and subjected them to genome-wide transcriptomic and proteomic profiling to identify key perturbations of normal physiology. We found that a rifampicin resistance-conferring mutation in RpoB imparts considerable gene expression changes, many of which are mitigated by a compensatory mutation in RpoC. However, our data also provide evidence for pervasive epistasis: the same resistance mutation imposed a different fitness cost and functionally unrelated changes to gene expression in clinical strains from unrelated genetic backgrounds. Rather than functional changes in specific pathways, our data suggest that the fitness cost of rifampicin resistance stems from a misallocation of resources: the greater the departure from the wild type baseline proteome investment, the greater the fitness cost of rifampicin resistance in a given strain. We summarize these observations in the “Burden of Expression” hypothesis of fitness cost and provide evidence that it can be used for suppressing the emergence of rifampicin resistance.
2021-03-12 | PXD011568 | Pride
Project description:The present study was aimed at analyzing (i) the biological cost of RNA polymerase (rpoB) mutations conferring rifampin resistance on H.pylori, (ii) the relationship between the cost of rpoB mutations and the chromosomal mutaion, (iii) the relationship between the cost of rpoB mutations and the transcription profile of sensitive and resistantrif strains of H.pylori (iv) and rpoB mutations in view of the possible fitness burden associated with resistance to another antibiotics. H.pylori reference strain 26695 was routinely maintained on Columbia agar plates and H. pylori-selective antibiotic mix Dent. Liquid culture was grown in BHI broth. Both plates and broth cultures were incubated at 37C under atmosphere enriched with 5% CO2 for 2-3 days . Mutant strains were selected by culturing H. pylori 26695 on selective plates containing rifampicin. In 5 days resistant colonies were picked up and passed under rifampicin pressure. RNA isolated was reverse transcribed and used to probe H. pylori home-made arrays
2010-11-30 | E-GEOD-25333 | biostudies-arrayexpress
Project description:The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa
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Project description:The present study was aimed at analyzing (i) the biological cost of RNA polymerase (rpoB) mutations conferring rifampin resistance on H.pylori, (ii) the relationship between the cost of rpoB mutations and the chromosomal mutaion, (iii) the relationship between the cost of rpoB mutations and the transcription profile of sensitive and resistantrif strains of H.pylori (iv) and rpoB mutations in view of the possible fitness burden associated with resistance to another antibiotics.
2010-11-30 | GSE25333 | GEO
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.
2021-11-25 | PXD027810 | Pride
Project description:Tuberculosis (TB) is still a major life-threatening infectious disease, within which especially the rise of multidrug resistant TB (MDR-TB) is currently worrying. This study focuses on mechanisms of development of rifampicin resistance, since rifampicin seems to play an important role in the development of MDR-TB. To provide further insight in rifampicin resistance, we performed a genome-wide transcriptional profile analysis for Mycobacterium tuberculosis (M. tuberculosis) using microarray technology and qRT-PCR analysis. We exposed a rifampicin-susceptible H37Rv wild type (H37Rv-WT) and a rifampicin-resistant progeny H37Rv strain with a H526Y mutation in the rpoB gene (H37Rv-H526Y) to several concentrations of rifampicin, to define the effect of rifampicin on the transcription profile. Our study showed that there are resistance-dependant differences in response between both M. tuberculosis strains. Gene clusters associated with efflux, transport and virulence were altered in the rifampicin-resistant H37Rv mutant compared to the rifampicin-susceptible H37Rv-WT strain after exposure to rifampicin. We conclude that the small gene cluster Rv0559c-Rv0560c in the H37Rv-H526Y strain was remarkably up-regulated in the microarray analysis and qRT-PCR results and appeared to be dependent on rifampicin concentration and time of exposure. Therefore this study suggests that Rv0559c and Rv0560c play a pivotal role in rifampicin resistance of M. tuberculosis. Further investigation of Rv0559c and Rv0560c is needed to reveal function and mechanism of both genes that were triggered upon rifampicin exposure. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-139]
2013-04-21 | E-BUGS-139 | biostudies-arrayexpress
Project description:Tuberculosis is one of top causes of death among curable infectious diseases; it is an airborne infectious disease that kills 2 million people worldwide. Anti-tuberculosis drug-induced liver injury is the primary cause of drug-induced liver injury (DILI). Rifampicin is one of the most common anti-tuberculosis therapies and has well-known hepatotoxicity. To understand the mechanism of rifampicin-induced liver injury, we performed a global proteomic analysis of liver proteins by LC-MS/MS in a mouse model after the oral administration of 177 and 442.5 mg/kg rifampicin (LD10 and LD25) for 14 days. Based on the biochemical parameters in the plasma after rifampicin treatment, the hepatotoxic effect of rifampicin in the mouse liver was defined as a mixed liver injury. In the present study, we identified 1,101 proteins and quantified 1,038 proteins. A total of 29 and 40 proteins were up-regulated and 27 and 118 proteins were down-regulated in response to 177 and 442.5 mg/kg rifampicin, respectively.
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Project description:The fidelity of signal transmission requires the binding of regulatory molecules to their cognate targets. However, the crowded cell interior risks off-target interactions between proteins that are functionally unrelated. Understanding the constraints this imposes on cell systems evolution requires the fitness cost of spurious interactions to be quantified. Towards this end, we express human tyrosine kinases in the budding yeast S. cerevisiae. Yeast lacks bona fide tyrosine kinases and so the majority of resulting pY sites are functionless and artificial. We express 24 unique tyrosine kinases in total and perform phosphoproteomics in each case, resulting in ~30,000 phosphosites sites mapping to 3500 phosphoproteins. Examination of the fitness costs in each strain reveals a strong correlation between the number of spurious pY sites generated and negative effects on growth. Moreover, the prediction of pY effects on protein structure and on protein function (conservation-based) reveals potential for the widespread perturbation of the yeast proteome. Comparing the spurious pY sites (pre-selection) with native pY sites in human (post-selection) also demonstrates the recurrent modification of proteins and sites with no homology to native substrates. However, examination of these data together (fitness and phosphoproteomics) strongly suggests that a large number of the pY sites generated have a negligible effect on fitness. Finally, we test the hypothesis of pY counter-selection following the emergence of tyrosine kinases in metazoan species, but find no strong evidence for proteome-wide selection against spurious Y phosphorylation.
2024-09-12 | PXD045466 | Pride
Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug Rifampicin. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.
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