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

Autor: Arianna Tocchetti, Marianna Iorio, Zeeshan Hamid, Andrea Armirotti, Angelo Reggiani, Stefano Donadio
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Molecules, Vol 26, Iss 22, p 6764 (2021)
Druh dokumentu: article
ISSN: 1420-3049
37212540
DOI: 10.3390/molecules26226764
Popis: 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.
Databáze: Directory of Open Access Journals
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