PXD070266

PXD070266 is an original dataset announced via ProteomeXchange.

Title	Itaconate-driven metabolic reprogramming boosts anti-infective therapeutic efficacy
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.
HostingRepository	iProX
AnnounceDate	2025-11-04
AnnouncementXML	Submission_2025-11-03_18:44:31.517.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tianqi Xu
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-11-03 18:43:31	ID requested
⏵ 1	2025-11-03 18:44:32	announced

Dataset with its publication pending

submitter keyword: antibiotic

colistin

drug-resistant bacteria

metabolic reprogramming

macrophage polarization

itaconate

Yuan Liu
contact affiliation	Yangzhou University
contact email	liuyuan2018@yzu.edu.cn
lab head
Tianqi Xu
contact affiliation	Yangzhou University
contact email	tianqi_xu@126.com
dataset submitter

iProX dataset URI