{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T14:46:55Z","timestamp":1775486815770,"version":"3.50.1"},"reference-count":65,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"The Danish Research Council for Independent Research, FTP","award":["0136-00200B"],"award-info":[{"award-number":["0136-00200B"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Infections caused by methicillin-resistant\n              <jats:italic>Staphylococcus aureus<\/jats:italic>\n              (MRSA) are a leading cause of mortality worldwide. MRSA has acquired resistance to next-generation \u03b2-lactam antibiotics through the horizontal acquisition of the\n              <jats:italic>mecA<\/jats:italic>\n              resistance gene. Development of high resistance is, however, often associated with additional mutations in a set of chromosomal core genes, known as potentiators, which, through poorly described mechanisms, enhance resistance. The\n              <jats:italic>yjbH<\/jats:italic>\n              gene was recently identified as a hot spot for adaptive mutations during severe infections. Here, we show that inactivation of\n              <jats:italic>yjbH<\/jats:italic>\n              increased \u03b2-lactam MICs up to 16-fold and transformed MRSA cells with low levels of resistance to being homogenously highly resistant to \u03b2-lactams. The\n              <jats:italic>yjbH<\/jats:italic>\n              gene encodes an adaptor protein that targets the transcriptional stress regulator Spx for degradation by the ClpXP protease. Using CRISPR interference (CRISPRi) to knock down\n              <jats:italic>spx<\/jats:italic>\n              transcription, we unambiguously linked hyper-resistance to the accumulation of Spx. Spx was previously proposed to be essential; however, our data suggest that Spx is dispensable for growth at 37\u00b0C but becomes essential in the presence of antibiotics with various targets. On the other hand, high Spx levels bypassed the role of PBP4 in \u03b2-lactam resistance and broadly decreased MRSA susceptibility to compounds targeting the cell wall or the cell membrane, including vancomycin, daptomycin, and nisin. Strikingly, Spx potentiated resistance independently of its redox-sensing switch. Collectively, our study identifies a general stress pathway that, in addition to promoting the development of high-level, broad-spectrum \u03b2-lactam resistance, also decreases MRSA susceptibility to critical antibiotics of last resort.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.00335-24","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T13:01:59Z","timestamp":1714568519000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["The Spx stress regulator confers high-level \u03b2-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin-resistant\n            <i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","author":[{"given":"Tobias Krogh","family":"Nielsen","sequence":"first","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ida Birkj\u00e6r","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4741-8418","authenticated-orcid":true,"given":"Maria Disen","family":"Barbuti","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, \u00c5s, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viktor","family":"Mebus","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anni","family":"Justh","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulelah Ahmed","family":"Alqarzaee","sequence":"additional","affiliation":[{"name":"Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Jacques","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiology, GIGA Institute, University of Li\u00e8ge Hospital, Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9cile","family":"Oury","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiology, GIGA Institute, University of Li\u00e8ge Hospital, Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7886-0727","authenticated-orcid":true,"given":"Vinai","family":"Thomas","sequence":"additional","affiliation":[{"name":"Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4448-9082","authenticated-orcid":true,"given":"Morten","family":"Kjos","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, \u00c5s, 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Bakker VD","year":"2023","unstructured":"Liu X. Bakker VD, Heggenhougen MV, M\u00e5rli MT, Fr\u00f8ynes AH, Salehian Z, Porcellato D, Angeles DM, Veening JW, Kjos M. 2023 Genome-wide crispri screens reveal the essentialome and determinants for susceptibility to dalbavancin in Staphylococcus aureus. bioRxiv. https:\/\/www.biorxiv.org\/content\/10.1101\/2023.08.30.555613v1.","journal-title":"bioRxiv"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.plasmid.2014.08.001"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.02370-16"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600081"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00335-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00335-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T13:02:24Z","timestamp":1714568544000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.00335-24"}},"subtitle":[],"editor":[{"given":"Benjamin P.","family":"Howden","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,5]]},"references-count":65,"alternative-id":["10.1128\/aac.00335-24"],"URL":"https:\/\/doi.org\/10.1128\/aac.00335-24","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5]]},"assertion":[{"value":"2024-03-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00335-24"}}