Project description:Untargeted metabolomics dataset for the paper "Metabolic mutations induce antibiotic resistance by pathway-specific bottlenecks "
These are the raw files for metabolites of all 41 isolates in Figure 4b of the paper.
Project description:Compilation of the targeted metabolomics data present in the associated paper: Metabolic mutations induce antibiotic resistance by pathway-specific bottlenecks.
See "File names association" table in "supplementary files" to link file names with paper figures.
Project description:Microarray experiment for pharmacogenomics profilling. Two mutations, an NF1 knockout and NRAS G12D, that induce the RAS signalling pathway were made in TF1 cells. The NRAS G12D mutant was treated with pyrvinium at 250 nM in DMSO (vehicle).
Project description:Cancer-associated mutations in the spliceosome gene create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we provide evidence that aberrant splicing by mutant alters the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also find that mutant induces vulnerability to deprivation of the nonessential amino acid serine, which is mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability is manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice is able to inhibit the growth ofMUT xenografts. These findings describe a novel role for mutations in altered energy metabolism, and they offer a new therapeutic strategy againstMUT cancers.
Project description:Bacteria have developed resistance against every antibiotic at a rate that is alarming considering the timescale at which new antibiotics are developed. Thus, there is a critical need to use antibiotics more effectively, extend the shelf life of existing antibiotics and minimize their side effects. This requires understanding the mechanisms underlying bacterial drug responses. Past studies have focused on survival in the presence of antibiotics by individual cells, as genetic mutants or persisters. Also important, however, is the fact that a population of bacterial cells can collectively survive antibiotic treatments lethal to individual cells. This tolerance can arise by diverse mechanisms, including resistance-conferring enzyme production, titration-mediated bistable growth inhibition, swarming and interpopulation interactions. These strategies can enable rapid population recovery after antibiotic treatment and provide a time window during which otherwise susceptible bacteria can acquire inheritable genetic resistance. Here, we emphasize the potential for targeting collective antibiotic tolerance behaviors as an antibacterial treatment strategy.