{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:30:46Z","timestamp":1790677846012,"version":"4.1.0"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2012,12,1]],"date-time":"2012-12-01T00:00:00Z","timestamp":1354320000000},"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":[[2012,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The incidence of hospital-acquired infections with multidrug-resistant (MDR) Gram-negative pathogens is increasing at an alarming rate. Equally alarming is the overall lack of efficacious therapeutic options for clinicians, which is due primarily to the acquisition and development of various antibiotic resistance mechanisms that render these drugs ineffective. Among these mechanisms is the reduced permeability of the outer membrane, which prevents many marketed antibiotics from traversing this barrier. To circumvent this, recent drug discovery efforts have focused on conjugating a siderophore moiety to a pharmacologically active compound that has been designed to hijack the bacterial siderophore transport system and trick cells into importing the active drug by recognizing it as a nutritionally beneficial compound. MC-1, a novel siderophore-conjugated \u03b2-lactam that promotes its own uptake into bacteria, has exquisite activity against many Gram-negative pathogens. While the inclusion of the siderophore was originally designed to facilitate outer membrane penetration into Gram-negative cells, here we show that this structural moiety also renders other clinically relevant antibiotic resistance mechanisms unable to affect MC-1 efficacy. Resistance frequency determinations and subsequent characterization of first-step resistant mutants identified PiuA, a TonB-dependent outer membrane siderophore receptor, as the primary means of MC-1 entry into\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Pseudomonas aeruginosa<\/jats:named-content>\n                    . While the MICs of these mutants were increased 32-fold relative to the parental strain\n                    <jats:italic>in vitro<\/jats:italic>\n                    , we show that this resistance phenotype is not relevant\n                    <jats:italic>in vivo<\/jats:italic>\n                    , as alternative siderophore-mediated uptake mechanisms compensated for the loss of PiuA under iron-limiting conditions.\n                  <\/jats:p>","DOI":"10.1128\/aac.01345-12","type":"journal-article","created":{"date-parts":[[2012,10,2]],"date-time":"2012-10-02T02:20:19Z","timestamp":1349144419000},"page":"6334-6342","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":91,"title":["Clinically Relevant Gram-Negative Resistance Mechanisms Have No Effect on the Efficacy of MC-1, a Novel Siderophore-Conjugated Monocarbam"],"prefix":"10.1128","volume":"56","author":[{"given":"Craig J.","family":"McPherson","sequence":"first","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Aschenbrenner","sequence":"additional","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Lacey","sequence":"additional","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly C.","family":"Fahnoe","sequence":"additional","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret M.","family":"Lemmon","sequence":"additional","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Finegan","sequence":"additional","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baswanth","family":"Tadakamalla","sequence":"additional","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"O'Donnell","sequence":"additional","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Mueller","sequence":"additional","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Tomaras","sequence":"additional","affiliation":[{"name":"Antibacterials Research Unit, Pfizer Worldwide Research &amp; Development, Groton, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0003-2697(91)90207-A","article-title":"Calorimetric determination of cooperative interactions in high affinity binding processes","volume":"192","author":"Bains G","year":"1991","unstructured":"BainsG FreireE. 1991. Calorimetric determination of cooperative interactions in high affinity binding processes. Anal. Biochem. 192:203\u2013206.","journal-title":"Anal. Biochem."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/160.3.823"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.6.1868-1871.2001"},{"key":"e_1_3_3_5_2","doi-asserted-by":"crossref","first-page":"574","DOI":"10.7164\/antibiotics.43.574","article-title":"Structure-activity relationships of some arylglycine analogues and catechol isosteres of BRL 36650, a 6 alpha-formamido penicillin","volume":"43","author":"Best DJ","year":"1990","unstructured":"BestDJ. 1990. Structure-activity relationships of some arylglycine analogues and catechol isosteres of BRL 36650, a 6 alpha-formamido penicillin. J. Antibiot. (Tokyo) 43:574\u2013577.","journal-title":"J. Antibiot. 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