{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:53:13Z","timestamp":1778028793960,"version":"3.51.4"},"reference-count":38,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2012,9,1]],"date-time":"2012-09-01T00:00:00Z","timestamp":1346457600000},"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":[[2012,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The resistance of methicillin-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Staphylococcus aureus<\/jats:named-content>\n            (MRSA) to all \u03b2-lactam classes limits treatment options for serious infections involving this organism. Our goal is to discover new agents that restore the activity of \u03b2-lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin), which potentiate the activity of imipenem against MRSA strain COL. We report here that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems. A synthetic derivative of actinocarbasin, M131, synergized with imipenem both\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            with potent efficacy. The\n            <jats:italic>in vitro<\/jats:italic>\n            activity of M131 extends to clinical isolates of MRSA but not to a methicillin-sensitive strain. Synergy is restricted to \u03b2-lactam antibiotics and is not observed with other antibiotic classes. We propose that the SpsB inhibitors synergize with \u03b2-lactams by preventing the signal peptidase-mediated secretion of proteins required for \u03b2-lactam resistance. Combinations of SpsB inhibitors and \u03b2-lactams may expand the utility of these widely prescribed antibiotics to treat MRSA infections, analogous to \u03b2-lactamase inhibitors which restored the utility of this antibiotic class for the treatment of resistant Gram-negative infections.\n          <\/jats:p>","DOI":"10.1128\/aac.00726-12","type":"journal-article","created":{"date-parts":[[2012,6,19]],"date-time":"2012-06-19T03:51:19Z","timestamp":1340077879000},"page":"4662-4670","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":76,"title":["Broadening the Spectrum of \u03b2-Lactam Antibiotics through Inhibition of Signal Peptidase Type I"],"prefix":"10.1128","volume":"56","author":[{"given":"Alex G.","family":"Therien","sequence":"first","affiliation":[{"name":"Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joann L.","family":"Huber","sequence":"additional","affiliation":[{"name":"Merck Research Laboratories, Rahway, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth E.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Merck Research Laboratories, Rahway, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Beaulieu","sequence":"additional","affiliation":[{"name":"Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandre","family":"Caron","sequence":"additional","affiliation":[{"name":"Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Claveau","sequence":"additional","affiliation":[{"name":"Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen","family":"Deschamps","sequence":"additional","affiliation":[{"name":"Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert G. 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