作者: Corti, Giorgio ; Donadio, Stefano ; Bonezzi, Fabiola ; Bertorelli, Rosalia ; Tarozzo, Glauco ; Monciardini, Paolo ; Iorio, Marianna ; Sosio, Margherita ; Brunati, Cristina ; Bordoni, Roberta ; Piomelli, Daniele ; Reggiani, Angelo ; Summa, Maria ; Sasso, Oscar ; Maffioli, Sonia I.

Among the growing family of ribosomally synthesized, post-translationally modified peptides, particularly intriguing are class III lanthipeptides containing the triamino acid labionin. In the course of a screening program aimed at finding bacterial cell wall inhibitors, we discovered a new lanthipeptide produced by an Actinoplanes sp. The molecule, designated NAI-112, consists of 22 amino acids and contains an N-terminal labionin and a C-terminal methyl-labionin. Unique among lanthipeptides, it carries a 6-deoxyhexose moiety N-linked to a tryptophan residue. Consistently, the corresponding gene cluster encodes, in addition to the LanKC enzyme characteristic of this lanthipeptide class, a glycosyl transferase. Despite possessing weak antibacterial activity, NAI-112 is effective in experimental models of nociceptive pain, reducing pain symptoms in mice in both the formalin and the chronic constriction injury tests. Thus, NAI-112 represents, after the labyrinthopeptins, the second example of a lanthipeptide effective against nociceptive pain.

Molecules3区 · 化学

Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity

3区 · 化学

ArticleOA

作者: Tocchetti, Arianna ; Hamid, Zeeshan ; Reggiani, Angelo ; Iorio, Marianna ; Donadio, Stefano ; Armirotti, Andrea

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 Staphylococcus aureus 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 S. aureus 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.

Organic & Biomolecular Chemistry3区 · 化学

Substrate tolerance of the biosynthetic enzymes of glycosylated lanthipeptide NAI-112

3区 · 化学

Article

作者: Liu, Bin ; Chen, Shaoming ; Wang, Huan ; Sheng, Wangjian ; Xu, Bing ; Li, Yuqing

NAI-112 is a glycosylated class III lanthipeptide produced by an Actinoplanes sp. strain with potent bioactivity against nociceptive pain.

100 项与 NAI-112 相关的药物交易

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