{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T02:21:46Z","timestamp":1789006906807,"version":"build-2803163510"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006014","name":"College of Medicine and Health Sciences, United Arab Emirates University","doi-asserted-by":"publisher","award":["G00003542 and G00003430"],"award-info":[{"award-number":["G00003542 and G00003430"]}],"id":[{"id":"10.13039\/501100006014","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Cefiderocol (CFDC) is a novel siderophore-cephalosporin, effective against multidrug-resistant Gram-negative bacteria. As it has a siderophore side chain, it can utilize iron acquisition systems for penetration of the bacterial outer membrane. We aimed to elucidate the role of siderophores and iron uptake receptors in defining <jats:italic>Klebsiella pneumoniae<\/jats:italic> susceptibility to CFDC.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Initially, 103 <jats:italic>K<\/jats:italic>. <jats:italic>pneumoniae<\/jats:italic> strains were characterized for susceptibility to different antibiotics including CFDC. CFDC minimum inhibitory concentrations (MIC) were determined in iron-depleted and iron-enriched conditions. Iron uptake genes including siderophores, their receptors, ferric citrate (<jats:italic>fecA<\/jats:italic>) and iron uptake (<jats:italic>kfu<\/jats:italic>) receptors were detected by PCR in all the strains. For 10 selected strains, gene expression was tested in iron-depleted media with or without CFDC treatment and compared to expression in iron-enriched conditions.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>CFDC exhibited 96.1% susceptibility, being superior to all the other antibiotics (MIC<jats:sub>50<\/jats:sub>: 0.5 and MIC<jats:sub>90<\/jats:sub>: 4 \u03bcg\/ml). Only three strains (2.9%) were intermediately susceptible and a pandrug resistant strain (0.97%) was resistant to CFDC (MIC: 8 and 256 \u03bcg\/ml, respectively). The presence of <jats:italic>kfu<\/jats:italic> and <jats:italic>fecA<\/jats:italic> had a significant impact on CFDC MIC, especially when co-produced, and if coupled with yersiniabactin receptor (<jats:italic>fyuA<\/jats:italic>). CFDC MICs were negatively correlated with enterobactin receptor (<jats:italic>fepA<\/jats:italic>) expression and positively correlated with expression of <jats:italic>kfu<\/jats:italic> and <jats:italic>fecA<\/jats:italic>. Thus, <jats:italic>fepA<\/jats:italic> was associated with increased susceptibility to CFDC, while <jats:italic>kfu<\/jats:italic> and <jats:italic>fecA<\/jats:italic> were associated with reduced susceptibility to CFDC. CFDC MICs increased significantly in iron-enriched media, with reduced expression of siderophore receptors, hence, causing less drug uptake.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Iron acquisition systems have a significant impact on CFDC activity, and their altered expression is a factor leading to reduced susceptibility. Iron concentration is also a major player affecting CFDC susceptibility; therefore, it is essential to explore possible ways to improve the drug activity to facilitate its use to treat infections in iron-rich sites.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0277946","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T18:29:40Z","timestamp":1672338580000},"page":"e0277946","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":40,"title":["Elucidating the effect of iron acquisition systems in Klebsiella pneumoniae on susceptibility to the novel siderophore-cephalosporin 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Ayoub","family":"Moubareck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akela","family":"Ghazawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Collyns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"pone.0277946.ref001","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1016\/j.drudis.2019.08.004","article-title":"Superbugs but no drugs: steps in averting a post-antibiotic era","volume":"24","author":"M Hamad","year":"2019","journal-title":"Drug Discov Today"},{"key":"pone.0277946.ref002","doi-asserted-by":"crossref","first-page":"21003824","DOI":"10.1016\/j.ijantimicag.2021.106421.111","article-title":"PGN-015\u2014Cefiderocol: A new weapon to fight antibiotic resistant Klebsiella 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