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

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 kno...

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Autores principales:	Arianna Tocchetti, Marianna Iorio, Zeeshan Hamid, Andrea Armirotti, Angelo Reggiani, Stefano Donadio
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	lanthipeptide untargeted lipidomics lysophosphatidic acid TPRV1 lipid II VISA strains Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/9f0b0a372125406d8ba46ba0a7a89b68
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spelling	oai:doaj.org-article:9f0b0a372125406d8ba46ba0a7a89b682021-11-25T18:27:05ZUnderstanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity10.3390/molecules262267641420-3049https://doaj.org/article/9f0b0a372125406d8ba46ba0a7a89b682021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/22/6764https://doaj.org/toc/1420-3049NAI-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 <i>Staphylococcus aureus</i> 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 <i>S. aureus</i> 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.Arianna TocchettiMarianna IorioZeeshan HamidAndrea ArmirottiAngelo ReggianiStefano DonadioMDPI AGarticlelanthipeptideuntargeted lipidomicslysophosphatidic acidTPRV1lipid IIVISA strainsOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6764, p 6764 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	lanthipeptide untargeted lipidomics lysophosphatidic acid TPRV1 lipid II VISA strains Organic chemistry QD241-441
spellingShingle	lanthipeptide untargeted lipidomics lysophosphatidic acid TPRV1 lipid II VISA strains Organic chemistry QD241-441 Arianna Tocchetti Marianna Iorio Zeeshan Hamid Andrea Armirotti Angelo Reggiani Stefano Donadio Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity
description	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 <i>Staphylococcus aureus</i> 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 <i>S. aureus</i> 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.
format	article
author	Arianna Tocchetti Marianna Iorio Zeeshan Hamid Andrea Armirotti Angelo Reggiani Stefano Donadio
author_facet	Arianna Tocchetti Marianna Iorio Zeeshan Hamid Andrea Armirotti Angelo Reggiani Stefano Donadio
author_sort	Arianna Tocchetti
title	Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity
title_short	Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity
title_full	Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity
title_fullStr	Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity
title_full_unstemmed	Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity
title_sort	understanding the mechanism of action of nai-112, a lanthipeptide with potent antinociceptive activity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/9f0b0a372125406d8ba46ba0a7a89b68
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Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity

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