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Free fatty acid generation via Rhein-induced LDL-C endocytosis accelerates biofilm infected diabetic wound healing

ABSTRACT:

Diabetic foot infection (DFI) significantly increases risks of hospitalization and amputation, with biofilm infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacteriaceae (CRE) being key drivers of treatment failure. Here, we analyze MRSA/CRE biofilm-infected ulcer tissues in patients using proteomics and metabolomics. Compared to non-healing cases, healed tissues show activation of the low-density lipoprotein receptor (LDLR)-mediated low-density lipoprotein cholesterol (LDL-C) endocytosis and increase free fatty acids production, which we hypothesize a potential countermeasure against biofilms. However, free fatty acids’ oxidative instability limits their therapeutic use. Building on our findings demonstrating Rhein’s potent anti-MRSA/CRE activity and its synergy with Ag⁺, we develop an injectable hydrogel for sustained co-delivery of both agents. This formulation outperforms Ag⁺ monotherapy, accelerating wound closure in biofilm-infected diabetic wounds. Mechanistically, Rhein binds to LDLR, upregulates its expression, and enhances LDL-C endocytosis pathway in vascular endothelial cells to generate more free fatty acids. Among these, eicosapentaenoic acid (EPA) is identified as the most critical free fatty acids promoting healing, as it inhibits biofilm formation and synergizes with Ag⁺ to exert antibacterial and pro-healing effects. Collectively, this study identifies endogenous host lipid metabolites as “metabolic antibiotics” and establishes a synergistic therapeutic strategy that concurrently suppresses biofilm formation, inhibits planktonic bacteria, alleviates inflammation, and promotes tissue repair in drug-resistant biofilm infected diabetic wounds.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13611 | MetaboLights | 2026-01-06

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13611_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13611_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13611_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13611_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Bacterial infections of wounds are associated with poor healing and worse scarring. We sought to identify transcriptomic patterns associated with impaired healing of wounds infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) using a rabbit ear wound model. Wounds created on post-operative day (POD) 0 were infected on POD3, within the inflammatory phase of healing. On POD4 the infected wounds were harvested for microarray/transcriptome analysis. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12. On POD4 before antibiotic treatment, both wounds contained elevated transcripts that enriched predominantly into inflammation/infection-response pathways and functions characteristic of infiltrating leukocytes. But there were 5-fold more elevated transcripts in P.a.- than K.p.-infected wounds. Additionally, unique to P.a.-infected wounds, was a minor network of inflammation/infection-response molecules with predicted upstream regulation predominated by type I interferons. Also on POD4, Dnr-transcripts of both wounds were enriched into stress-response pathways such as EIF2 signaling. But there were 8-fold more Dnr-transcripts in P.a.- than K.p.-infected wounds, and many more of them enriched in the function, cell death, suggesting that resident dermal cells of P.a.-infected wounds failed to survive a more destructive P.a. infection. On POD6, following two days of antibiotic treatment, the biofilm-colonized wounds expressed magnitudes fewer inflammation and stress-response transcripts. However, a single regulatory network of P.a.-infected wounds was found to consist of Upr-transcripts enriching immune/infection-response functions predicted to be regulated by type I interferons, which was similar to the network unique to P.a.-infected wounds on POD4. On POD12, genes expressed by K.p.-infected wounds suggesting healing, while for P.a.-infected wounds they suggested stalled healing. The similarities and differences between the wound responses to these infections further define the molecular foundations of healing impaired by infections. Rabbit ear Wounds created on post-operative day (POD) 0 were infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) on POD3 and harvested on POD4 for RNA extraction. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12.

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Free fatty acid generation via Rhein-induced LDL-C endocytosis accelerates biofilm infected diabetic wound healing

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