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In this study, we screened actinomycetes isolated from Hegura Island, Ishikawa Prefecture, Japan, to discover new antibiotics through combined-culture with <jats:italic>Tsukamurella pulmonis<\/jats:italic> TP-B0596. Three new phenazine-class antibiotics, griseoluteins T (<jats:bold>1<\/jats:bold>), C (<jats:bold>2<\/jats:bold>), and D (<jats:bold>3<\/jats:bold>), along with two known related metabolites, griseoluteic acid (<jats:bold>4<\/jats:bold>) and griseolutein A (<jats:bold>5<\/jats:bold>), were detected in both mono- and combined-cultures of <jats:italic>Streptomyces seoulensis<\/jats:italic> HEK131 with <jats:italic>T. pulmonis<\/jats:italic> at different production levels. Detailed spectroscopic analysis revealed that <jats:bold>1<\/jats:bold> contained a dihydrophenazine core, and was converted to <jats:bold>5<\/jats:bold> by accepting oxidation spontaneously. <jats:bold>1<\/jats:bold>, containing a dihydrophenazine group, was relatively unstable under oxidative conditions, and the addition of ascorbate was required during the isolation of the compound. <jats:bold>2<\/jats:bold> and <jats:bold>3<\/jats:bold> were found to be cysteine-adducts analogous to <jats:bold>4<\/jats:bold>, and their productivity was increased in the combined-culture. We further assessed the antibacterial activities of <jats:bold>1<\/jats:bold> against clinically significant Gram-positive pathogenic bacteria, including 30 methicillin-resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (MRSA), 27 vancomycin-resistant <jats:italic>Enterococci<\/jats:italic> (VRE), and 17 <jats:italic>Clostridioides difficile<\/jats:italic>. Notably, <jats:bold>1<\/jats:bold> was found to possess higher antibacterial activity against these microorganisms than several clinically important antibiotics, while displaying lower cytotoxicity against HeLa-S3 cells.<\/jats:p>","DOI":"10.1038\/s41429-025-00846-3","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T08:46:57Z","timestamp":1752137217000},"page":"542-551","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Griseolutein T from Streptomyces seoulensis, newly identified via combined-culture with Tsukamurella pulmonis, as an efficacious therapeutic agent against multidrug-resistant bacteria"],"prefix":"10.1038","volume":"78","author":[{"given":"Sung-Jin","family":"Kawai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7178-5410","authenticated-orcid":false,"given":"Shumpei","family":"Asamizu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4536-1881","authenticated-orcid":false,"given":"Hiroyasu","family":"Onaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshichika","family":"Arakawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouji","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Ojika","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"846_CR1","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.mib.2019.10.008","volume":"51","author":"MI Hutchings","year":"2019","unstructured":"Hutchings MI, Truman AW, Wilkinson B. 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