The World Health Organization has listed antibiotic resistance as one of the top ten health threats. There is an urgent need to analyze the resistance mechanism to develop novel anti-infection strategies. Fatty acids have been reported to promote antibiotic resistance; however, the underlying mechanism is complex and requires further exploration. To address this, we investigated the effect of sodium oleate-mediated resistance by proteomics. The present study corroborated that sodium oleate decreased the sensitivity of E. coli to gentamicin being visualized by fluorescence imaging, bacterial survival curve and minimum inhibitory concentration (MIC) assays. Proteomic profiles after treatment with gentamicin or sodium oleate were significantly different, with a number of proteins significantly changing. Pathway enrichment analysis showed that fatty acid biosynthesis and the stress response were upregulated under gentamicin treatment, whereas sodium oleate upregulated fatty acid degradation, amino acids metabolism, siderophore transmembrane transporter activity and enterobactin biosynthetic process. The addition of sodium oleate increased the expression levels of genes involved in the fatty acid degradation pathway by qPCR. Additionally, sodium linoleate and sodium palmitate also reduced bacterial sensitivity to gentamicin. The higher level of acetyl-CoA was found, and acetic acid/sodium acetate also reduced bacterial sensitivity to gentamicin, which was associated with protein acetylation. Moreover, sodium oleate caused a decrease in membrane potential and porin permeability, thereby affecting gentamicin uptake. This study provides new insights of fatty acid-mediated resistance, which may contribute to the development of novel strategies for addressing antibiotic resistance.
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