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Lactate-driven lysine lactylation mediates high-level colistin resistance in Salmonella

ABSTRACT: 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.

ORGANISM(S): Salmonella Enterica Subsp. Enterica Serovar Typhimurium Str. 798

SUBMITTER: Yuan Liu

PROVIDER: PXD079853 | iProX | Thu Jun 18 00:00:00 BST 2026

REPOSITORIES: iProX

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Lactate-driven lysine lactylation mediates high-level colistin resistance in Salmonella

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

Lactate-driven lysine lactylation mediates high-level colistin resistance in Salmonella

2026-06-17 | PXD079846 |

Lactate regulates cell differentiation of erythroid progenitor cells via histone lactylation modification [CUT&Tag]

Project description:As a key metabolite of glycolysis, lactate plays important regulatory roles in a variety of biological events by regulating metabolic homeostasis and histone lactylation. However, the role of lactate and histone lactylation in human erythropoiesis remains unclear. Here, we explored the role of lactate in erythropoiesis by adding the glycolysis inhibitor 2-DG or exogenous lactate Na-La to decrease or increase intracellular lactate levels, respectively. The results showed that 2-DG treatment promoted erythroid progenitors differentiation, blocked cell cycle and reduced colony-forming ability of CFU-E. In contrast, Na-La delayed erythroid progenitors differentiation and promoted CFU-E colony formation. We also found that lactate levels directly regulated H3K14la and H3K18la intensity. Furthermore, CUT&Tag results showed that the lost H3K14la peaks after 2-DG treatment were mainly enriched in promoter region and were associated with cell cycle and division. RNA-seq results showed that gene expression pattern was dramatically altered after 2-DG treatment, and differentially expressed genes were enriched in cell cycle and division process. Integrated analysis of CUT&Tag and RNA-seq revealed that gene expression was regulated by H3K14la, and CCNB1, CFL1, CENPA, SKA2 and GNAI2 gene expression were verified by RT-qPCR. In conclusion, our study reveals that lactate affects the cell differentiation of early erythroid progenitors by regulating gene expression through histone lactylation.

2025-05-17 | GSE274165 | GEO

Lactate regulates cell differentiation of erythroid progenitor cells via histone lactylation modification [RNA-seq]

2025-05-17 | GSE274169 | GEO

Polymerase occupancy (ChIP-Seq) in WT and mutants of Caulobacter crescentus NA1000

Project description:Coordination of cell cycle progression with central metabolism is fundamental to all cell types and likely underlies differentiation into dispersal cells in bacteria. How central metabolism is monitored to regulate cell cycle functions is poorly understood. A forward genetic selection for cell cycle regulators in the polarized alpha-proteobacterium Caulobacter crescentus unearthed the uncharacterized CitA citrate synthase, a TCA (tricarboxylic acid) cycle enzyme, as unprecedented checkpoint regulator of the G1→S transition. We show that loss of the CitA protein provokes a (p)ppGpp alarmone-dependent G1-phase arrest without apparent metabolic or energy insufficiency. While S-phase entry is still conferred when CitA is rendered catalytically inactive, the paralogous CitB citrate synthase has no overt role other than sustaining TCA cycle activity when CitA is absent. With eukaryotic citrate synthase paralogs known to fulfill regulatory functions, our work extends the moonlighting paradigm to citrate synthase coordinating central (TCA) metabolism with development and perhaps antibiotic tolerance in bacteria.

2020-03-19 | GSE144533 | GEO

Itaconate-driven metabolic reprogramming boosts anti-infective therapeutic efficacy

Project description:Antibiotic therapy is highly effective for treating infectious diseases, but the key factors determining its clinical efficacy are not fully understood. Here, we show that itaconate (ITA), a metabolite produced by macrophages, has dual anti-infective effects against multidrug-resistant Klebsiella pneumoniae both in vitro and in vivo. In bacteria, ITA activates the TCA cycle and respiratory complex I, increasing intracellular pH. This downregulates molecular chaperones DksA and DnaK, suppresses the RpoS-mediated stress response, and restores colistin susceptibility against mcr-positive bacteria. In the host, ITA induces glycolytic reprogramming and lactate accumulation in infected macrophages, driving protein lactylation and promoting the pro-inflammatory M1 phenotype. Lysine lactylation of serine hydroxymethyltransferase 2 (SHMT2), a mitochondrial enzyme involved in one-carbon metabolism, is a key event linking ITA metabolism to immune activation. Lactylated SHMT2 inhibits prolyl hydroxylase (PHD) activity, stabilizes HIF-1α, and activates downstream transcriptional programs, including TNF and PTGS2, thereby enhancing M1 polarization. Genetic deletion or K464R mutation of SHMT2 abolishes these effects and negates ITA-induced bacterial clearance. Our findings reveal a ITA-driven metabolic reprogramming strategy that simultaneously reprograms bacterial metabolism to reverse colistin resistance and activates the SHMT2–HIF-1α axis via lactylation to boost macrophage antimicrobial responses.

2025-11-04 | PXD070266 |

Itaconate-driven metabolic reprogramming can enhance the efficacy of anti-infective treatments

2025-11-04 | PXD070276 |

Lactylation of Tau in Human Alzheimers Disease Brain

Project description:Aggregation of phosphorylated tau is associated with cognitive impairment in Alzheimers disease patients. In AD a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post-translational modification on proteins that conjugates lactyl groups to lysine residues known as lactylation. Our findings suggest that tau lactylation links metabolic dysregulation with tauopathies and could serve as a novel diagnostic and therapeutic target.

| MSV000095881 | MassIVE

Lactate-Driven Protein Lactylation Regulates Virulence in Plasmodium falciparum

Project description:Lactic acidosis, driven by hyperlactatemia, is a hallmark of severe Plasmodium falciparum malaria, yet its impact on parasitic life cycle and gene expression remains unclear. In mammalian cells, lactate influences transcription through histone lactylation, a novel post-translational modification. In this study, we demonstrate that P. falciparum undergoes lactate-derived lysine lactylation on nuclear proteins, including histones, histone variants, and AP2 transcription factors, with lactylation levels dynamically varying in response to physiological lactate ranges. Through CUT&RUN profiling, we show that elevated lactate enhances chromatin occupancy of lactylated proteins at promoters of genes involved in virulence and cytoadherence. Correspondingly, transcriptomic analyses demonstrated a suppression of these genes in response to elevated lactate, a pattern also evident in clinical isolates from severe malaria patients. Functionally, we demonstrate that high lactate reduces the binding ability of infected erythrocytes to CD36 receptor. Together, our findings reveal protein lactylation as a metabolite-responsive epigenetic mechanism in P. falciparum, linking host metabolic state to transcriptional reprogramming with direct implications for parasite virulence and disease pathogenesis.

2025-08-08 | GSE304394 | GEO

Integration of epigenome and lactylome reveals the regulation of lipid production in Nannochloropsis oceanica

Project description:Lysine lactylation (Kla) is a kind of novel post-translational modification (PTM), which participates in gene expression and various metabolic processes. Nannochloropsis, a significant oleaginous microalgae of economic significance, demonstrates a remarkable capacity for triacylglycerol (TAG) production under nitrogen stress. To elucidate the involvement of lactylation in lipid synthesis, we conducted ChIP-seq and mRNA-seq analyses to monitor lactylation modifications and transcriptome alterations in Nannochloropsis oceanica. In all, 2,057 genes showed considerable variation between nitrogen deprivation (ND) and nitrogen repletion (NR) conditions, comprising 853 upregulated genes and 1,204 downregulated genes. Moreover, a total of 5,375 differential Kla peaks were identified, including 5,331 gain peaks and 44 loss peaks under ND vs NR. The differential Kla peaks were primarily distributed in the promoter (<= 1 kb) (71.07%), 5’UTR (22.64%), and exon (4.25%). Integrative analysis of ChIP-seq, transcriptome, and previous proteome and lactylome data elucidates the potential mechanism by which lactylation promotes lipid accumulation under ND. Lactylation facilitates autophagy and protein degradation, leading to the recycling of carbon into the tricarboxylic acid (TCA) cycle, thereby providing carbon precursors for lipid synthesis. Additionally, lactylation induces the redirection of carbon from membrane lipids to TAG by upregulating lipases and enhancing the TCA cycle and β-oxidation pathways. This research reveals the regulatory functions of lactylation in lipid metabolism and gene expression in Nannochloropsis, offering a new perspective for the investigation of lipid biosynthesis.

2024-06-26 | GSE261019 | GEO

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