E.coli and Salmonella colistin resistance
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ABSTRACT:
PROVIDER: PRJEB18587 | ENA |
REPOSITORIES: ENA
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Project description:Intracellular pathogens are particularly refractory to antibiotic eradication, leading to persistent and relapsing infections. However, how intracellular metabolic microenvironments shape antibiotic resistance phenotypes remains poorly understood. Here we delineate a metabolic-regulatory axis wherein Salmonella Typhimurium undergoes profound metabolic rewiring upon intramacrophage adaptation, suppressing oxidative phosphorylation and the tricarboxylic acid (TCA) cycle while upregulating anaerobic glycolysis. This metabolic shift generates elevated lactate levels that drive widespread lysine lactylation, including modifications on the two-component system regulators PmrA and PmrD. Lactylation at specific residues stabilizes phosphorylated PmrA, thereby activating lipopolysaccharide modification genes that remodel the outer membrane charge to confer high-level colistin resistance. Critically, metabolic intervention with exogenous citrate restores TCA cycle activity, reduces lactate production and subsequent PmrA/D lactylation, and resensitizes bacteria to colistin both in vitro and in vivo. These findings reveal metabolic reprogramming as a deterministic driver of post-translational regulatory networks governing antibiotic resistance, offering a paradigm for targeting bacterial metabolism to combat drug-resistant bacteria.
2026-06-17 | MTBLS14781 | MetaboLights
Project description:Intracellular pathogens are particularly refractory to antibiotic eradication, leading to persistent and relapsing infections. However, how intracellular metabolic microenvironments shape antibiotic resistance phenotypes remains poorly understood. Here we delineate a metabolic-regulatory axis wherein Salmonella Typhimurium undergoes profound metabolic rewiring upon intramacrophage adaptation, suppressing oxidative phosphorylation and the tricarboxylic acid (TCA) cycle while upregulating anaerobic glycolysis. This metabolic shift generates elevated lactate levels that drive widespread lysine lactylation, including modifications on the two-component system regulators PmrA and PmrD. Lactylation at specific residues stabilizes phosphorylated PmrA, thereby activating lipopolysaccharide modification genes that remodel the outer membrane charge to confer high-level colistin resistance. Critically, metabolic intervention with exogenous citrate restores TCA cycle activity, reduces lactate production and subsequent PmrA/D lactylation, and resensitizes bacteria to colistin both in vitro and in vivo. These findings reveal metabolic reprogramming as a deterministic driver of post-translational regulatory networks governing antibiotic resistance, offering a paradigm for targeting bacterial metabolism to combat drug-resistant bacteria.
| PXD079846 |
Project description:Intracellular pathogens are particularly refractory to antibiotic eradication, leading to persistent and relapsing infections. However, how intracellular metabolic microenvironments shape antibiotic resistance phenotypes remains poorly understood. Here we delineate a metabolic-regulatory axis wherein Salmonella Typhimurium undergoes profound metabolic rewiring upon intramacrophage adaptation, suppressing oxidative phosphorylation and the tricarboxylic acid (TCA) cycle while upregulating anaerobic glycolysis. This metabolic shift generates elevated lactate levels that drive widespread lysine lactylation, including modifications on the two-component system regulators PmrA and PmrD. Lactylation at specific residues stabilizes phosphorylated PmrA, thereby activating lipopolysaccharide modification genes that remodel the outer membrane charge to confer high-level colistin resistance. Critically, metabolic intervention with exogenous citrate restores TCA cycle activity, reduces lactate production and subsequent PmrA/D lactylation, and resensitizes bacteria to colistin both in vitro and in vivo. These findings reveal metabolic reprogramming as a deterministic driver of post-translational regulatory networks governing antibiotic resistance, offering a paradigm for targeting bacterial metabolism to combat drug-resistant bacteria.
| PXD079853 |
Project description:Colistin resistance in Enterobacterales
| PRJEB47075 | ENA
Project description:Polymyxins are increasingly used as the critical last-resort therapeutic options for multidrug-resistant gram-negative bacteria. Unfortunately, polymyxin resistance has increased gradually for the last few years. Although studies on mechanisms of polymyxin are expanding, system-wide analyses of the underlying mechanism for polymyxin resistance and stress response are still lacking. To understand how Klebsiella pneumoniae adapt to colistin (polymyxin E) pressure, we carried out proteomic analysis of Klebsiella pneumoniae strain cultured with different concentrations of colistin. Our results showed that the proteomic responses to colistin treatment in Klebsiella pneumoniae involving several pathways, including (i) gluconeogenesis and TCA cycle; (ii) arginine biosynthesis; (iii) porphyrin and chlorophyll metabolism; and (iv) enterobactin biosynthesis. Interestingly, decreased abundance of class A β-lactamases including TEM, SHV-11, SHV-4 were observed in cells treated with colistin. Moreover, we also present comprehensive proteome atlases of paired polymyxin-susceptible and -resistant Klebsiella pneumoniae strains. The polymyxin-resistant strain Ci, a mutant of Klebsiella pneumoniae ATCC BAA 2146, showed missense mutation in crrB. The crrB mutant Ci, which displayed lipid A modification with 4-amino-4-deoxy-L-arabinose (L-Ara4N) and palmitoylation, showed striking increases of CrrAB, PmrAB, PhoPQ, ArnBCADT and PagP. We hypothesize that crrB mutations induce elevated expression of the arnBCADTEF operon and pagP via PmrAB and PhoPQ. Moreover, multidrug efflux pump KexD, which was induced by crrB mutation, also contributed to colistin resistance. Overall, our results demonstrated proteomic responses to colistin treatment and the mechanism of CrrB-mediate colistin resistance, which may further offer valuable information to manage polymyxin resistance.
2022-04-11 | PXD018528 | Pride
Project description:Colistin resistance in Klebsiella pneumoniae
| PRJEB29521 | ENA
Project description:To explore how multiple drug-resistant A. baumannii response to colistin resistance, we compared the genomic, transcriptional and proteomic profile of A. baumannii MDR-ZJ06 to that of induced colistin resistant strain ZJ06-200P5-1.
2017-03-15 | PXD005265 | Pride
Project description:The transcriptional, epigenomic, and genomic profiles of K. pneumoniae isolates were characterised to identify novel colistin and carbapenem resistance mechanisms. The genomic DNA and total RNA of the isolates were isolated and sequenced on PacBio.
2022-11-07 | GSE217148 | GEO
Project description:Acinetobacter baumannii is often highly resistant to multiple antimicrobials, posing a risk of treatment failure, and colistin is a "last resort" for treatment of the bacterial infection. However, colistin resistance is easily developed when the bacteria are exposed to the drug, and a comprehensive analysis of colistin-mediated changes in colistin-susceptible and -resistant A. baumannii is needed. In this study, using an isogenic pair of colistin-susceptible and -resistant A. baumannii isolates, alterations in morphologic and transcriptomic characteristics associated with colistin resistance were revealed. Whole-genome sequencing showed that the resistant isolate harbored a PmrBL208F mutation conferring colistin resistance, and all other single-nucleotide alterations were located in intergenic regions. Using scanning electron microscopy, it was determined that the colistin-resistant mutant had a shorter cell length than the parental isolate, and filamented cells were found when both isolates were exposed to the inhibitory concentration of colistin. When the isolates were treated with inhibitory concentrations of colistin, more than 80% of the genes were upregulated, including genes associated with antioxidative stress response pathways. The results elucidate the morphological difference between the colistin-susceptible and -resistant isolates and different colistin-mediated responses in A. baumannii isolates depending on their susceptibility to this drug.
2025-05-02 | GSE267612 | GEO
Project description:Although several Acinetobacter baumannii lineages can acquire colistin resistance by eliminating LPS/LOS glycolipids, the widely used reference background ATCC 17978 is unable to access this trajectory under standard selection, suggesting that glycolipid essentiality is strongly context dependent. Here we show that this barrier is not absolute but instead reflects the structural state of the envelope. Disrupting phospholipid homeostasis, through loss of the Mla system, which mediates retrograde phospholipid transport, and the outer-membrane phospholipase PldA, which degrades mislocalized phospholipids, destabilizes lipid asymmetry and creates a fragile yet permissive state that enables the emergence of stable glycolipid-deficient, colistin-resistant variants.
2026-06-03 | GSE314574 | GEO