{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:55:20Z","timestamp":1792205720906,"version":"4.4.0"},"reference-count":0,"publisher":"S. Karger AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T00:00:00Z","timestamp":1670284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T00:00:00Z","timestamp":1670284800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Innate Immun"],"published-print":{"date-parts":[[2023]]},"abstract":"Methicillin-resistant <i>Staphylococcus aureus<\/i> (MRSA) has been classified as a high priority pathogen by the World Health Organization underlining the high demand for new therapeutics to treat infections. Human group IIA-secreted phospholipase A<sub>2<\/sub> (hGIIA) is among the most potent bactericidal proteins against Gram-positive bacteria, including <i>S. aureus<\/i>. To determine hGIIA-resistance mechanisms of MRSA, we screened the Nebraska Transposon Mutant Library using a sublethal concentration of recombinant hGIIA. We identified and confirmed the role of <i>lspA<\/i>, encoding the lipoprotein signal peptidase LspA, as a new hGIIA resistance gene in both in vitro assays and an infection model in hGIIA-transgenic mice. Increased susceptibility of the <i>lspA<\/i> mutant was associated with enhanced activity of hGIIA on the cell membrane. Moreover, <i>lspA<\/i> deletion increased susceptibility to daptomycin, a last-resort antibiotic to treat MRSA infections. MRSA wild type could be sensitized to hGIIA and daptomycin killing through exposure to LspA-specific inhibitors globomycin and myxovirescin A1. Analysis of &#x3e;26,000 <i>S. aureus<\/i> genomes showed that LspA is highly sequence-conserved, suggesting universal application of LspA inhibition. The role of LspA in hGIIA resistance was not restricted to MRSA since <i>Streptococcus mutans<\/i> and <i>Enterococcus faecalis<\/i> were also more hGIIA-susceptible after <i>lspA<\/i> deletion or LspA inhibition, respectively. Overall, our data suggest that pharmacological interference with LspA may disarm Gram-positive pathogens, including MRSA, to enhance clearance by innate host defense molecules and clinically applied antibiotics. <\/jats:p>","DOI":"10.1159\/000527549","type":"journal-article","created":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T22:00:33Z","timestamp":1670364033000},"page":"333-350","source":"Crossref","is-referenced-by-count":4,"title":["Interference with Lipoprotein Maturation Sensitizes Methicillin-Resistant <b><i>Staphylococcus aureus<\/i><\/b> to Human Group IIA-Secreted Phospholipase A<sub>2<\/sub> and Daptomycin"],"prefix":"10.1159","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8763-2702","authenticated-orcid":false,"given":"Marieke M.","family":"Kuijk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0050-8480","authenticated-orcid":false,"given":"Yongzheng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent P.","family":"van Hensbergen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5111-7458","authenticated-orcid":false,"given":"Gizem","family":"Shanlitourk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3640-5061","authenticated-orcid":false,"given":"Christine","family":"Payr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9239-518X","authenticated-orcid":false,"given":"G\u00e9rard","family":"Lambeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Man-Bovenkerk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Herrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1042-5665","authenticated-orcid":false,"given":"Rolf","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6253-0830","authenticated-orcid":false,"given":"Jos A.G.","family":"van Strijp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1154-652X","authenticated-orcid":false,"given":"Yvonne","family":"Pannekoek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lhousseine","family":"Touqui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2695-5863","authenticated-orcid":false,"given":"Nina M.","family":"van Sorge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2022,12,6]]},"container-title":["Journal of Innate Immunity"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/karger.com\/jin\/article-pdf\/15\/1\/333\/4124663\/000527549.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/karger.com\/jin\/article-pdf\/15\/1\/333\/4124663\/000527549.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T15:28:30Z","timestamp":1745422110000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000527549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,6]]},"references-count":0,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12,22]]}},"URL":"https:\/\/doi.org\/10.1159\/000527549","archive":["Portico"],"relation":{"is-supplemented-by":[{"id-type":"doi","id":"10.6084\/m9.figshare.21679874","asserted-by":"subject"}]},"ISSN":["1662-811X","1662-8128"],"issn-type":[{"value":"1662-811X","type":"print"},{"value":"1662-8128","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,6]]}}}