{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T10:59:18Z","timestamp":1762253958901,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["720776"],"award-info":[{"award-number":["720776"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/molecules26226764","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T12:46:23Z","timestamp":1636461983000},"page":"6764","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7004-7582","authenticated-orcid":false,"given":"Arianna","family":"Tocchetti","sequence":"first","affiliation":[{"name":"Naicons Srl, Viale Ortles 22\/4, 20139 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8669-5875","authenticated-orcid":false,"given":"Marianna","family":"Iorio","sequence":"additional","affiliation":[{"name":"Naicons Srl, Viale Ortles 22\/4, 20139 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeeshan","family":"Hamid","sequence":"additional","affiliation":[{"name":"D3 Validation, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Armirotti","sequence":"additional","affiliation":[{"name":"Analytical Chemistry Lab, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Reggiani","sequence":"additional","affiliation":[{"name":"D3 Validation, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Donadio","sequence":"additional","affiliation":[{"name":"Naicons Srl, Viale Ortles 22\/4, 20139 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1039\/C2NP20085F","article-title":"Ribosomally Synthesized and Post-Translationally Modified Peptide Natural Products: Overview and Recommendations for a Universal Nomenclature","volume":"30","author":"Arnison","year":"2013","journal-title":"Nat. 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