Naicons Srl, Viale Ortles 22/4, 20139 Milan, Italy.
D3 Validation, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
Molecules. 2021 Nov 9;26(22):6764. doi: 10.3390/molecules26226764.
NAI-112, a glycosylated, labionine-containing lanthipeptide with weak antibacterial activity, has demonstrated analgesic activity in relevant mouse models of nociceptive and neuropathic pain. However, the mechanism(s) through which NAI-112 exerts its analgesic and antibacterial activities is not known. In this study, we analyzed changes in the spinal cord lipidome resulting from treatment with NAI-112 of naive and in-pain mice. Notably, NAI-112 led to an increase in phosphatidic acid levels in both no-pain and pain models and to a decrease in lysophosphatidic acid levels in the pain model only. We also showed that NAI-112 can form complexes with dipalmitoyl-phosphatidic acid and that can become resistant to NAI-112 through serial passages at sub-inhibitory concentrations of the compound. The resulting resistant mutants were phenotypically and genotypically related to vancomycin-insensitive strains, suggesting that NAI-112 binds to the peptidoglycan intermediate lipid II. Altogether, our results suggest that NAI-112 binds to phosphate-containing lipids and blocks pain sensation by decreasing levels of lysophosphatidic acid in the TRPV1 pathway.
NAI-112 是一种糖基化的、含 labionine 的兰尼肽，具有较弱的抗菌活性，在相关的伤害感受性和神经性疼痛的小鼠模型中显示出镇痛活性。然而，NAI-112 发挥其镇痛和抗菌活性的机制尚不清楚。在这项研究中，我们分析了 NAI-112 处理未疼痛和疼痛小鼠的脊髓脂类组的变化。值得注意的是，NAI-112 导致无疼痛模型和疼痛模型中磷脂酸水平增加，而仅在疼痛模型中导致溶血磷脂酸水平降低。我们还表明，NAI-112 可以与二棕榈酰磷脂酸形成复合物，并且可以通过在低于化合物抑制浓度的连续传代而对 NAI-112 产生抗性。由此产生的抗性突变体在表型和基因型上与耐万古霉素的菌株有关，这表明 NAI-112 结合到肽聚糖中间体脂质 II。总的来说，我们的结果表明，NAI-112 结合到含磷酸盐的脂质上，并通过降低 TRPV1 途径中的溶血磷脂酸水平来阻断疼痛感觉。
