{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T19:02:09Z","timestamp":1761418929558},"reference-count":47,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T00:00:00Z","timestamp":1409529600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Glycopeptides and \u03b2-lactams inhibit bacterial peptidoglycan synthesis in Gram-positive bacteria; resistance to these antibiotics is studied intensively in enterococci and staphylococci because of their relevance to infectious disease. Much less is known about antibiotic resistance in glycopeptide-producing actinomycetes that are likely to represent the evolutionary source of resistance determinants found in bacterial pathogens.<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Nonomuraea<\/jats:named-content>sp. ATCC 39727, the producer of A40926 (the precursor for the semisynthetic dalbavancin), does not harbor the canonical<jats:italic>vanHAX<\/jats:italic>genes. Consequently, we investigated the role of the \u03b2-lactam-sensitive<jats:sc>d<\/jats:sc>,<jats:sc>d<\/jats:sc>-peptidase\/<jats:sc>d<\/jats:sc>,<jats:sc>d<\/jats:sc>-carboxypeptidase encoded by<jats:italic>vanY<jats:sub>n<\/jats:sub><\/jats:italic>, the only<jats:italic>van<\/jats:italic>-like gene found in the A40926 biosynthetic gene cluster, in conferring immunity to the antibiotic in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Nonomuraea<\/jats:named-content>sp. ATCC 39727. Taking advantage of the tools developed recently to genetically manipulate this uncommon actinomycete, we varied<jats:italic>vanY<jats:sub>n<\/jats:sub><\/jats:italic>gene dosage and expressed<jats:italic>vanH<jats:sub>at<\/jats:sub>A<jats:sub>at<\/jats:sub>X<jats:sub>at<\/jats:sub><\/jats:italic>from the teicoplanin producer<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Actinoplanes teichomyceticus<\/jats:named-content>in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Nonomuraea<\/jats:named-content>sp. ATCC 39727. Knocking out<jats:italic>vanY<jats:sub>n<\/jats:sub><\/jats:italic>, complementing a<jats:italic>vanY<jats:sub>n<\/jats:sub><\/jats:italic>mutant, or duplicating<jats:italic>vanY<jats:sub>n<\/jats:sub><\/jats:italic>had no effect on growth but influenced antibiotic resistance and, in the cases of complementation and duplication, antibiotic production.<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Nonomuraea<\/jats:named-content>sp. ATCC 39727 was found to be resistant to penicillins, but its glycopeptide resistance was diminished in the presence of penicillin G, which inhibits VanY<jats:sub>n<\/jats:sub>activity. The heterologous expression of<jats:italic>vanH<jats:sub>at<\/jats:sub>A<jats:sub>at<\/jats:sub>X<jats:sub>at<\/jats:sub><\/jats:italic>increased A40926 resistance in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Nonomuraea<\/jats:named-content>sp. ATCC 39727 but did not increase antibiotic production, indicating that the level of antibiotic production is not directly determined by the level of resistance. The<jats:italic>vanY<jats:sub>n<\/jats:sub><\/jats:italic>-based self-resistance in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Nonomuraea<\/jats:named-content>sp. ATCC 39727 resembles the glycopeptide resistance mechanism described recently in mutants of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Enterococcus faecium<\/jats:named-content>selected<jats:italic>in vitro<\/jats:italic>for high-level resistance to glycopeptides and penicillins.<\/jats:p>","DOI":"10.1128\/aac.02626-14","type":"journal-article","created":{"date-parts":[[2014,6,24]],"date-time":"2014-06-24T06:08:33Z","timestamp":1403590113000},"page":"5191-5201","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["Relationship between Glycopeptide Production and Resistance in the Actinomycete Nonomuraea sp. ATCC 39727"],"prefix":"10.1128","volume":"58","author":[{"given":"Giorgia Letizia","family":"Marcone","sequence":"first","affiliation":[{"name":"Dipartimento di Biotecnologie e Scienze della Vita, Universit\u00e0 degli Studi dell'Insubria, Varese, Italy"},{"name":"The Protein Factory Research Center, Politecnico di Milano, ICRM CNR Milano and Universit\u00e0 degli Studi dell'Insubria, Varese, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Binda","sequence":"additional","affiliation":[{"name":"Dipartimento di Biotecnologie e Scienze della Vita, Universit\u00e0 degli Studi dell'Insubria, Varese, Italy"},{"name":"The Protein Factory Research Center, Politecnico di Milano, ICRM CNR Milano and Universit\u00e0 degli Studi dell'Insubria, Varese, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Carrano","sequence":"additional","affiliation":[{"name":"Fondazione Istituto Insubrico Ricerca per la Vita, Insubrias BioPark, Gerenzano (VA), Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mervyn","family":"Bibb","sequence":"additional","affiliation":[{"name":"John Innes Centre, Norwich Research Park, Norwich, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavia","family":"Marinelli","sequence":"additional","affiliation":[{"name":"Dipartimento di Biotecnologie e Scienze della Vita, Universit\u00e0 degli Studi dell'Insubria, Varese, Italy"},{"name":"The Protein Factory Research Center, Politecnico di Milano, ICRM CNR Milano and Universit\u00e0 degli Studi dell'Insubria, Varese, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ja.2013.117"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.2174\/138920111796117382"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/978-3-642-39968-8_2","volume-title":"Antimicrobials\u2014new and old molecules in the fight against multi-resistant bacteria","author":"Rossolini GM","year":"2014","unstructured":"RossoliniGMArenaFPolliniS. 2014. 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