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Itaconate-driven metabolic reprogramming boosts anti-infective therapeutic efficacy

ABSTRACT: 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.

ORGANISM(S): Mus Musculus

SUBMITTER: Yuan Liu

PROVIDER: PXD070266 | iProX | Tue Nov 04 00:00:00 GMT 2025

REPOSITORIES: iProX

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