{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:50:55Z","timestamp":1790830255234,"version":"4.1.0"},"reference-count":127,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T00:00:00Z","timestamp":1711497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>We studied the <jats:italic>Escherichia coli<\/jats:italic> outer membrane protein Fiu, a presumed transporter of monomeric ferric catecholates, by introducing Cys residues in its surface loops and modifying them with fluorescein maleimide (FM). Fiu-FM bound iron complexes of the tricatecholate siderophore enterobactin (FeEnt) and glucosylated enterobactin (FeGEnt), their dicatecholate degradation product Fe(DHBS)<jats:sub>2<\/jats:sub> (FeEnt*), the monocatecholates dihydroxybenzoic acid (FeDHBA) and dihydroxybenzoyl serine (FeDHBS), and the siderophore antibiotics cefiderocol (FDC) and MB-1. Unlike high-affinity ligand-gated porins (LGPs), Fiu-FM had only micromolar affinity for iron complexes. Its apparent K<jats:sub>D<\/jats:sub> values for FeDHBS, FeDHBA, FeEnt*, FeEnt, FeGEnt, FeFDC, and FeMB-1 were 0.1, 0.7, 0.7, 1.0, 0.3, 0.4, and 4\u2009\u03bcM, respectively. Despite its broad binding abilities, the transport repertoires of <jats:italic>E. coli<\/jats:italic> Fiu, as well as those of Cir and FepA, were less broad. Fiu only transported FeEnt*. Cir transported FeEnt* and FeDHBS (weakly); FepA transported FeEnt, FeEnt*, and FeDHBA. Both Cir and FepA bound FeGEnt, albeit with lower affinity. Related transporters of <jats:italic>Acinetobacter baumannii<\/jats:italic> (PiuA, PirA, BauA) had similarly moderate affinity and broad specificity for di- or monomeric ferric catecholates. Both microbiological and radioisotopic experiments showed Fiu\u2019s exclusive transport of FeEnt*, rather than ferric monocatecholate compounds. Molecular docking and molecular dynamics simulations predicted three binding sites for FeEnt*in the external vestibule of Fiu, and a fourth site deeper in its interior. Alanine scanning mutagenesis in the outermost sites (1a, 1b, and 2) decreased FeEnt* binding affinity as much as 20-fold and reduced or eliminated FeEnt* uptake. Finally, the molecular dynamics simulations suggested a pathway of FeEnt* movement through Fiu that may generally describe the process of metal transport by TonB-dependent receptors.<\/jats:p>","DOI":"10.3389\/fmicb.2024.1355253","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T14:15:08Z","timestamp":1711548908000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Specificity and mechanism of TonB-dependent ferric catecholate uptake by Fiu"],"prefix":"10.3389","volume":"15","author":[{"given":"Taihao","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Leung","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salete M.","family":"Newton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip E.","family":"Klebba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"11524","DOI":"10.11510.11021\/ja803524w","article-title":"The siderocalin\/enterobactin interaction: a link between mammalian immunity and bacterial iron transport","volume":"130","author":"Abergel","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/S0021-9258(19)43074-3","article-title":"Resolution of bacterial proteins by polyacrylamide gel electrophoresis on slabs. Membrane, soluble, and periplasmic fractions","volume":"249","author":"Ames","year":"1974","journal-title":"J. Biol. Chem."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1085\/jgp.70.5.567","article-title":"Inactivation of the sodium channel. II. Gating current experiments","volume":"70","author":"Armstrong","year":"1977","journal-title":"J. Gen. Physiol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e0023423","DOI":"10.1128\/aac.00234-23","article-title":"Contribution of Iron-transport systems and \u03b2-lactamases to Cefiderocol resistance in clinical isolates of Acinetobacter baumannii endemic to new York City","volume":"67","author":"Asrat","year":"2023","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1126\/science.277.5331.1453","article-title":"The complete genome sequence of Escherichia coli K-12","volume":"277","author":"Blattner","year":"1997","journal-title":"Science (New York, N.Y.)"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1002\/j.1460-2075.1996.tb00535.x","article-title":"FhuA, a transporter of the Escherichia coli outer membrane, is converted into a channel upon binding of bacteriophage T5","volume":"15","author":"Bonhivers","year":"1996","journal-title":"EMBO J."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"3146","DOI":"10.1128\/jb.175.10.3146-3150.1993","article-title":"The proton motive force drives the outer membrane transport of cobalamin in Escherichia coli","volume":"175","author":"Bradbeer","year":"1993","journal-title":"J. Bacteriol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"4919","DOI":"10.1128\/jb.172.9.4919-4926.1990","article-title":"Interdependence of calcium and cobalamin binding by wild-type and mutant BtuB protein in the outer membrane of Escherichia coli","volume":"172","author":"Bradbeer","year":"1990","journal-title":"J. Bacteriol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/0014-5793(94)00431-5","article-title":"Energy-coupled transport through the outer membrane of Escherichia coli small deletions in the gating loop convert the FhuA transport protein into a diffusion channel","volume":"346","author":"Braun","year":"1994","journal-title":"FEBS Lett."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"12350","DOI":"10.1016\/S0021-9258(19)49846-3","article-title":"Overexpression and purification of ferric enterobactin esterase from Escherichia coli. Demonstration of enzymatic hydrolysis of enterobactin and its iron complex","volume":"267","author":"Brickman","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2594","DOI":"10.1038\/sj.emboj.7601693","article-title":"Structure of colicin I receptor bound to the R-domain of colicin Ia: implications for protein import","volume":"26","author":"Buchanan","year":"2007","journal-title":"EMBO J."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/4931","article-title":"Crystal structure of the outer membrane active transporter FepA from Escherichia coli [see comments]","volume":"6","author":"Buchanan","year":"1999","journal-title":"Nat. Struct. Biol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"73","DOI":"10.2174\/1568026013395524","article-title":"Siderophore-antibiotic conjugates used as trojan horses against Pseudomonas aeruginosa","volume":"1","author":"Budzikiewicz","year":"2001","journal-title":"Curr. Top. Med. Chem."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"10688","DOI":"10.1073\/pnas.1932538100","article-title":"Differential substrate-induced signaling through the TonB-dependent transporter BtuB","volume":"100","author":"Cadieux","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1074\/jbc.M210360200","article-title":"Spectroscopic observations of ferric enterobactin transport","volume":"278","author":"Cao","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"4394","DOI":"10.1128\/jb.173.14.4394-4403.1991","article-title":"Internal deletions in the FhuA receptor of Escherichia coli K-12 define domains of ligand interactions","volume":"173","author":"Carmel","year":"1991","journal-title":"J. Bacteriol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1111\/mmi.13059","article-title":"Catecholate siderophore esterases Fes, IroD and IroE are required for salmochelins secretion following utilization, but only IroD contributes to virulence of extra-intestinal pathogenic Escherichia coli","volume":"97","author":"Caza","year":"2015","journal-title":"Mol. Microbiol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1023\/A:1023485632520","article-title":"Identification and mutational studies of conserved amino acids in the outer membrane receptor protein, FepA, which affect transport but not binding of ferric-enterobactin in Escherichia coli","volume":"16","author":"Chakraborty","year":"2003","journal-title":"Biometals"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"4682","DOI":"10.1074\/jbc.RA118.006921","article-title":"Universal fluorescent sensors of high-affinity iron transport, applied to ESKAPE pathogens","volume":"294","author":"Chakravorty","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1038\/nsb914","article-title":"Substrate-induced transmembrane signaling in the cobalamin transporter BtuB","volume":"10","author":"Chimento","year":"2003","journal-title":"Nat. Struct. Biol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.jmb.2005.01.021","article-title":"The crystal structure of the pyoverdine outer membrane receptor FpvA from Pseudomonas aeruginosa at 3.6 angstroms resolution","volume":"347","author":"Cobessi","year":"","journal-title":"J. Mol. Biol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.jmb.2005.08.004","article-title":"Crystal structure at high resolution of ferric-pyochelin and its membrane receptor FptA from Pseudomonas aeruginosa","volume":"352","author":"Cobessi","year":"","journal-title":"J. Mol. Biol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1002\/prot.22539","article-title":"Structure of the heme\/hemoglobin outer membrane receptor ShuA from Shigella dysenteriae: heme binding by an induced fit mechanism","volume":"78","author":"Cobessi","year":"2010","journal-title":"Proteins"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1111\/j.1365-2958.1994.tb01320.x","article-title":"Iron piracy: acquisition of transferrin-bound iron by bacterial pathogens","volume":"14","author":"Cornelissen","year":"1994","journal-title":"Mol. Microbiol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"13524","DOI":"10.1074\/jbc.R111.311829","article-title":"Mammalian siderophores, siderophore-binding lipocalins, and the labile iron pool","volume":"287","author":"Correnti","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1128\/AAC.32.12.1879","article-title":"Iron-regulated outer membrane proteins of Escherichia coli K-12 and mechanism of action of catechol-substituted cephalosporins","volume":"32","author":"Curtis","year":"1988","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.1093\/jac\/dkaa117","article-title":"Activity of cefiderocol against high-risk clones of multidrug-resistant Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia","volume":"75","author":"Delgado-Valverde","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref28","first-page":"208","article-title":"Characterization of a noncovalent lipocalin complex by liquid chromatography\/electrospray ionization mass spectrometry","volume":"15","author":"Doneanu","year":"2004","journal-title":"J. Biomol. Tech."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0: new docking methods, expanded force field, and Python bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"30574","DOI":"10.1074\/jbc.M506708200","article-title":"Siderophore transport through Escherichia coli outer membrane receptor FhuA with disulfide-tethered cork and barrel domains","volume":"280","author":"Eisenhauer","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"4683","DOI":"10.1128\/JB.185.16.4683-4692.2003","article-title":"Mutant analysis of the Escherichia coli FhuA protein reveals sites of FhuA activity","volume":"185","author":"Endriss","year":"2003","journal-title":"J. Bacteriol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"639","DOI":"10.3390\/biomedicines11020639","article-title":"The Iron content of human serum albumin modulates the susceptibility of Acinetobacter baumannii to Cefiderocol","volume":"11","author":"Escalante","year":"2023","journal-title":"Biomedicines"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"11543","DOI":"10.1021\/bi0259397","article-title":"Structure and dynamics of the beta-barrel of the membrane transporter BtuB by site-directed spin labeling","volume":"41","author":"Fanucci","year":"2002","journal-title":"Biochemistry"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1016\/S0006-3495(03)74573-1","article-title":"Molecular dynamics simulations of the bacterial outer membrane protein FhuA: a comparative study of the ferrichrome-free and bound states","volume":"85","author":"Faraldo-G\u00f3mez","year":"2003","journal-title":"Biophys. J."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1715","DOI":"10.1126\/science.1067313","article-title":"Structural basis of gating by the outer membrane transporter FecA","volume":"295","author":"Ferguson","year":"2002","journal-title":"Science (New York, N.Y.)"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1126\/science.282.5397.2215","article-title":"Siderophore-mediated iron transport: crystal structure of FhuA with bound lipopolysaccharide [see comments]","volume":"282","author":"Ferguson","year":"1998","journal-title":"Science (New York, N.Y.)"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1097\/TA.0000000000001338","article-title":"Modeling Acinetobacter baumannii wound infections: the critical role of iron","volume":"82","author":"Fleming","year":"2017","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1128\/IAI.06279-11","article-title":"Role of acinetobactin-mediated iron acquisition functions in the interaction of Acinetobacter baumannii strain ATCC 19606T with human lung epithelial cells, galleria mellonella caterpillars, and mice","volume":"80","author":"Gaddy","year":"2012","journal-title":"Infect. Immun."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"19523","DOI":"10.1074\/jbc.RA119.011018","article-title":"The structure of the bacterial iron-catecholate transporter Fiu suggests that it imports substrates via a two-step mechanism","volume":"294","author":"Grinter","year":"","journal-title":"J. Biol. Chem."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1107\/S2052252519002926","article-title":"Determination of the molecular basis for coprogen import by gram-negative bacteria","volume":"6","author":"Grinter","year":"","journal-title":"IUCrJ"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1107\/S2059798320004398","article-title":"The crystal structure of the TonB-dependent transporter YncD reveals a positively charged substrate-binding site","volume":"76","author":"Grinter","year":"2020","journal-title":"Acta Crystallogr. D Struct. Biol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"6526","DOI":"10.1128\/jb.171.12.6526-6533.1989","article-title":"Point mutations in a conserved region (TonB box) of Escherichia coli outer membrane protein BtuB affect vitamin B12 transport","volume":"171","author":"Gudmundsdottir","year":"1989","journal-title":"J. Bacteriol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1529\/biophysj.107.104158","article-title":"Mechanics of force propagation in TonB-dependent outer membrane transport","volume":"93","author":"Gumbart","year":"2007","journal-title":"Biophys. J."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1093\/jac\/dkac022","article-title":"Relationship of TonB-dependent receptors with susceptibility to cefiderocol in clinical isolates of Pseudomonas aeruginosa","volume":"77","author":"Gupta","year":"2022","journal-title":"J. Antimicrob. Chemother."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/0014-5793(76)80481-4","article-title":"The colicin I receptor of Escherichia coli K-12 has a role in enterochelin-mediated iron transport","volume":"65","author":"Hancock","year":"1976","journal-title":"FEBS Lett."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1177\/1087057115613788","article-title":"High-throughput screening assay for inhibitors of TonB-dependent Iron transport","volume":"21","author":"Hanson","year":"2016","journal-title":"J. Biomol. Screen."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1007\/BF00334830","article-title":"Identification of an iron uptake system specific for coprogen and rhodotorulic acid in Escherichia coli K12","volume":"191","author":"Hantke","year":"1983","journal-title":"Mol. Gen. Genet."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/0378-1097(90)90158-m","article-title":"Dihydroxybenzoylserine--a siderophore for E. coli","volume":"55","author":"Hantke","year":"1990","journal-title":"FEMS Microbiol. Lett."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"3677","DOI":"10.1073\/pnas.0737682100","article-title":"Salmochelins, siderophores of salmonella enterica and uropathogenic Escherichia coli strains, are recognized by the outer membrane receptor IroN","volume":"100","author":"Hantke","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1021\/ja00502a053","article-title":"Spectrophotometric determination of the proton-dependent stability constant of ferric enterobactin","volume":"101","author":"Harris","year":"1979","journal-title":"J. Am. Chem. Soc."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.str.2004.10.009","article-title":"Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration","volume":"13","author":"Holmes","year":"2005","journal-title":"Structure"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1128\/jb.151.3.1591-1594.1982","article-title":"Analysis of btuB receptor function by use of nonsense suppression","volume":"151","author":"Hunter","year":"1982","journal-title":"J. Bacteriol."},{"key":"ref53","article-title":"Changes of responsible Iron-transporters for the activity of Cefiderocol against Pseudomonas aeruginosa depending on the culture conditions","volume-title":"ASM Microbe","author":"Ito","year":"2019"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"e01454","DOI":"10.1128\/AAC.01454-17","article-title":"In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against gram-negative bacteria","volume":"62","author":"Ito","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"297","DOI":"10.4155\/fmc.11.191","article-title":"Exploiting bacterial iron acquisition: siderophore conjugates","volume":"4","author":"Ji","year":"2012","journal-title":"Future Med. Chem."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1126\/science.276.5316.1261","article-title":"Ligand-specific opening of a gated-porin channel in the outer membrane of living bacteria","volume":"276","author":"Jiang","year":"1997","journal-title":"Science (New York, N.Y.)"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1086\/514006","article-title":"Discovery of disseminated J96-like strains of uropathogenic Escherichia coli O4: H5 containing genes for both PapGJ96 (class I) and PrsGJ96 (class III) gal (\u03b11-4) gal-binding adhesins","volume":"175","author":"Johnson","year":"1997","journal-title":"J. Infect. Dis."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"11553","DOI":"10.1073\/pnas.1304243110","article-title":"Energy-dependent motion of TonB in the gram-negative bacterial inner membrane","volume":"110","author":"Jordan","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1021\/ja00214a001","article-title":"The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin","volume":"110","author":"Jorgensen","year":"1988","journal-title":"J. Am. Chem. Soc."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"7743","DOI":"10.1128\/AAC.00831-15","article-title":"Pharmacodynamic profiling of a siderophore-conjugated monocarbam in Pseudomonas aeruginosa: assessing the risk for resistance and attenuated efficacy","volume":"59","author":"Kim","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref61","volume-title":"Regulation of the bisynthesis of the iron-related membrane proteins in","author":"Klebba","year":"1981"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"s1422","DOI":"10.2741\/1233","article-title":"Three paradoxes of ferric enterobactin uptake","volume":"8","author":"Klebba","year":"2003","journal-title":"Front. Biosci."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1128\/JB.00823-15","article-title":"ROSET model of TonB action in gram-negative bacterial Iron acquisition","volume":"198","author":"Klebba","year":"2016","journal-title":"J. Bacteriol."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1128\/jb.149.3.880-888.1982","article-title":"Kinetics of biosynthesis of iron-regulated membrane proteins in Escherichia coli","volume":"149","author":"Klebba","year":"1982","journal-title":"J. Bacteriol."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"5193","DOI":"10.1021\/acs.chemrev.0c01005","article-title":"Iron acquisition systems of gram (\u2212) bacterial pathogens define TonB-dependent pathways to novel antibiotics","volume":"121","author":"Klebba","year":"2021","journal-title":"Chem. Rev."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"101651","DOI":"10.1016\/j.jbc.2022.101651","article-title":"Fluorescent sensors of siderophores produced by bacterial pathogens","volume":"298","author":"Kumar","year":"2022","journal-title":"J. Biol. Chem."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s11908-020-0716-3","article-title":"Carbapenem-resistant Enterobacterales: considerations for treatment in the era of new antimicrobials and evolving enzymology","volume":"22","author":"Lasko","year":"2020","journal-title":"Curr. Infect. Dis. Rep."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"600","DOI":"10.3390\/biomedicines10030600","article-title":"Human serum proteins and susceptibility of Acinetobacter baumannii to Cefiderocol: role of Iron transport","volume":"10","author":"Le","year":"2022","journal-title":"Biomedicines"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"11075","DOI":"10.1021\/ja0522027","article-title":"In vitro characterization of salmochelin and enterobactin trilactone hydrolases IroD, IroE, and Fes","volume":"127","author":"Lin","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/S0092-8674(00)81700-6","article-title":"Transmembrane signaling across the ligand-gated FhuA receptor: crystal structures of free and ferrichrome-bound states reveal allosteric changes","volume":"95","author":"Locher","year":"1998","journal-title":"Cell"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","article-title":"OPLS4: improving force field accuracy on challenging regimes of chemical space","volume":"17","author":"Lu","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/0014-5793(75)80272-9","article-title":"Electrophoretic resolution of the \"major outer membrane protein\" of Escherichia coli K12 into four bands","volume":"58","author":"Lugtenberg","year":"1975","journal-title":"FEBS Lett."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"2631","DOI":"10.1093\/jac\/dkz225","article-title":"Adjunctive transferrin to reduce the emergence of antibiotic resistance in gram-negative bacteria","volume":"74","author":"Luna","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"e00097-18","DOI":"10.1128\/AAC.00097-18","article-title":"TonB-dependent receptor repertoire of Pseudomonas aeruginosa for uptake of Siderophore-drug conjugates","volume":"62","author":"Luscher","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref75","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1074\/jbc.M605333200","article-title":"Evidence of ball-and-chain transport of ferric enterobactin through FepA","volume":"282","author":"Ma","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"i21","DOI":"10.1093\/jacamr\/dlab055","article-title":"Compassionate use of cefiderocol for carbapenem-resistant Acinetobacter baumannii prosthetic joint infection","volume":"3","author":"Mabayoje","year":"2021","journal-title":"JAC Antimicrob. Resist."},{"key":"ref77","doi-asserted-by":"publisher","first-page":"4974","DOI":"10.1074\/jbc.RA119.011850","article-title":"Conformational rearrangements in the N-domain of Escherichia coli FepA during ferric enterobactin transport","volume":"295","author":"Majumdar","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"e01221-20","DOI":"10.1128\/AAC.01221-20","article-title":"Cefiderocol resistance in Acinetobacter baumannii: roles of \u03b2-lactamases, Siderophore receptors, and penicillin binding protein 3","volume":"64","author":"Malik","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"e0217120","DOI":"10.1128\/AAC.02171-20","article-title":"New perspectives on antimicrobial agents: Cefiderocol","volume":"65","author":"McCreary","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/0006-291X(76)91144-X","article-title":"Effect of iron of the relative abundance of two large polypeptides of the Escherichia coli outer membrane","volume":"70","author":"McIntosh","year":"1976","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref81","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1021\/acs.accounts.1c00004","article-title":"Design and syntheses of new antibiotics inspired by Nature's quest for Iron in an oxidative climate","volume":"54","author":"Miller","year":"2021","journal-title":"Acc. Chem. Res."},{"key":"ref82","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1007\/BF01135559","article-title":"The design, synthesis and study of siderophore-antibiotic conjugates. Siderophore mediated drug transport","volume":"4","author":"Miller","year":"1991","journal-title":"Biol. Met."},{"key":"ref83","doi-asserted-by":"publisher","first-page":"28391","DOI":"10.1074\/jbc.272.45.28391","article-title":"Cell envelope signaling in Escherichia coli. Ligand binding to the ferrichrome-iron receptor fhua promotes interaction with the energy- transducing protein TonB","volume":"272","author":"Moeck","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref84","doi-asserted-by":"publisher","first-page":"e01649-20","DOI":"10.1128\/JCM.01649-20","article-title":"Cefiderocol antimicrobial susceptibility testing against multidrug-resistant gram-negative Bacilli: a comparison of disk diffusion to broth microdilution","volume":"59","author":"Morris","year":"2020","journal-title":"J. Clin. Microbiol."},{"key":"ref85","doi-asserted-by":"publisher","first-page":"e00889-16","DOI":"10.1128\/JB.00889-16","article-title":"Fluorescence high-throughput screening for inhibitors of TonB action","volume":"199","author":"Nairn","year":"2017","journal-title":"J. Bacteriol."},{"key":"ref86","doi-asserted-by":"publisher","first-page":"2776","DOI":"10.1128\/IAI.01095-06","article-title":"Extraintestinal pathogenic Escherichia coli survives within neutrophils","volume":"75","author":"Nazareth","year":"2007","journal-title":"Infect. Immun."},{"key":"ref87","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1128\/jb.119.3.736-747.1974","article-title":"Culture medium for enterobacteria","volume":"119","author":"Neidhardt","year":"1974","journal-title":"J. Bacteriol."},{"key":"ref88","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/B978-0-12-515250-1.50006-0","article-title":"Iron and its role in microbial physiology","volume-title":"Microbial iron metabolism","author":"Neilands","year":"1974"},{"key":"ref89","doi-asserted-by":"publisher","first-page":"26723","DOI":"10.1074\/jbc.270.45.26723","article-title":"Siderophores: structure and function of microbial iron transport compounds","volume":"270","author":"Neilands","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref90","doi-asserted-by":"publisher","first-page":"4560","DOI":"10.1073\/pnas.94.9.4560","article-title":"Double mutagenesis of a positive charge cluster in the ligand-binding site of the ferric enterobactin receptor, FepA","volume":"94","author":"Newton","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1046\/j.1365-2958.1999.01424.x","article-title":"Effect of loop deletions on the binding and transport of ferric enterobactin by FepA","volume":"32","author":"Newton","year":"1999","journal-title":"Mol. Microbiol."},{"key":"ref92","doi-asserted-by":"publisher","first-page":"e4543","DOI":"10.21769\/BioProtoc.4543","article-title":"Fluorescent binding protein sensors for detection and quantification of biochemicals, metabolites, and natural products","volume":"12","author":"Newton","year":"2022","journal-title":"Bio Protoc."},{"key":"ref93","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1111\/j.1365-2958.2004.04436.x","article-title":"The svpA-srtB locus of Listeria monocytogenes: Fur-mediated iron regulation and effect on virulence","volume":"55","author":"Newton","year":"2005","journal-title":"Mol. Microbiol."},{"key":"ref94","doi-asserted-by":"publisher","first-page":"17488","DOI":"10.1074\/jbc.M109.100206","article-title":"Direct measurements of the outer membrane stage of ferric enterobactin transport: postuptake binding","volume":"285","author":"Newton","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref95","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1128\/jb.172.3.1361-1367.1990","article-title":"Cir and Fiu proteins in the outer membrane of Escherichia coli catalyze transport of monomeric catechols: study with beta-lactam antibiotics containing catechol and analogous groups","volume":"172","author":"Nikaido","year":"1990","journal-title":"J. Bacteriol."},{"key":"ref96","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1146\/annurev.micro.112408.134247","article-title":"TonB-dependent transporters: regulation, structure, and function","volume":"64","author":"Noinaj","year":"2010","journal-title":"Ann. Rev. Microbiol."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1016\/j.bpj.2020.08.034","article-title":"Native cell environment constrains loop structure in the Escherichia coli cobalamin transporter BtuB","volume":"119","author":"Nyenhuis","year":"2020","journal-title":"Biophys. J."},{"key":"ref98","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1126\/science.1128057","article-title":"Structure of TonB in complex with FhuA, E. coli outer membrane receptor","volume":"312","author":"Pawelek","year":"2006","journal-title":"Science"},{"key":"ref99","doi-asserted-by":"publisher","first-page":"21950","DOI":"10.1074\/jbc.272.35.21950","article-title":"Biphasic binding kinetics between FepA and its ligands","volume":"272","author":"Payne","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref100","doi-asserted-by":"publisher","first-page":"1896","DOI":"10.1002\/cbic.201500147","article-title":"Discovery and characterization of new Hydroxamate Siderophores, Baumannoferrin A and B, produced by Acinetobacter baumannii","volume":"16","author":"Penwell","year":"2015","journal-title":"Chembiochem"},{"key":"ref101","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.3389\/fmicb.2019.01599","article-title":"Identification of potential virulence factors in the model strain Acinetobacter baumannii A118","volume":"10","author":"Ramirez","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref102","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1111\/j.1365-2958.1993.tb01696.x","article-title":"Generation of isogenic K54 capsule-deficient Escherichia coli strains through TnphoA-mediated gene disruption","volume":"9","author":"Russo","year":"1993","journal-title":"Mol. Microbiol."},{"key":"ref103","doi-asserted-by":"publisher","first-page":"7156","DOI":"10.1128\/IAI.70.12.7156-7160.2002","article-title":"IroN functions as a siderophore receptor and is a urovirulence factor in an extraintestinal pathogenic isolate of Escherichia coli","volume":"70","author":"Russo","year":"2002","journal-title":"Infect. Immun."},{"key":"ref104","doi-asserted-by":"publisher","first-page":"3325","DOI":"10.1128\/IAI.00430-15","article-title":"Aerobactin, but not yersiniabactin, salmochelin, or enterobactin, enables the growth\/survival of hypervirulent (hypermucoviscous) Klebsiella pneumoniae ex vivo and in vivo","volume":"83","author":"Russo","year":"2015","journal-title":"Infect. Immun."},{"key":"ref105","doi-asserted-by":"publisher","first-page":"e26734","DOI":"10.26710.21371\/journal.pone.0026734","article-title":"Hypervirulent K. pneumoniae secretes more and more active iron-acquisition molecules than \"classical\" K. pneumoniae thereby enhancing its virulence","volume":"6","author":"Russo","year":"2011","journal-title":"PLoS One"},{"key":"ref106","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1126\/science.1411544","article-title":"Formation of a gated channel by a ligand-specific transport protein in the bacterial outer membrane","volume":"258","author":"Rutz","year":"1992","journal-title":"Science (New York, N.Y.)"},{"key":"ref107","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Sastry","year":"2013","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref108","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.tibs.2008.04.012","article-title":"New substrates for TonB-dependent transport: do we only see the 'tip of the iceberg'?","volume":"33","author":"Schauer","year":"2008","journal-title":"Trends Biochem. Sci."},{"key":"ref109","doi-asserted-by":"publisher","first-page":"4906","DOI":"10.1128\/JB.184.17.4906-4911.2002","article-title":"Surface loop motion in FepA","volume":"184","author":"Scott","year":"2002","journal-title":"J. Bacteriol."},{"key":"ref110","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1111\/j.1365-2958.1991.tb00788.x","article-title":"Nucleotide sequence and genetic organization of the ferric enterobactin transport system: homology to other periplasmic binding protein- dependent systems in Escherichia coli","volume":"5","author":"Shea","year":"1991","journal-title":"Mol. Microbiol."},{"key":"ref111","doi-asserted-by":"publisher","first-page":"e00059-20","DOI":"10.1128\/AAC.00059-20","article-title":"Case commentary: the need for Cefiderocol is clear, but are the supporting clinical data?","volume":"64","author":"Shields","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref112","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1126\/science.1127694","article-title":"Outer membrane active transport: structure of the BtuB:TonB complex","volume":"312","author":"Shultis","year":"2006","journal-title":"Science"},{"key":"ref113","doi-asserted-by":"publisher","first-page":"e00951-20","DOI":"10.1128\/JCM.00951-20","article-title":"Cefiderocol antimicrobial susceptibility testing considerations: the Achilles' heel of the Trojan horse?","volume":"59","author":"Simner","year":"2020","journal-title":"J. Clin. Microbiol."},{"key":"ref114","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1085\/jgp.201311159","article-title":"Concerted loop motion triggers induced fit of FepA to ferric enterobactin","volume":"144","author":"Smallwood","year":"2014","journal-title":"J. Gen. Physiol."},{"key":"ref115","doi-asserted-by":"publisher","first-page":"e1261","DOI":"10.1093\/cid\/ciac647","article-title":"Evolution and transmission of Cefiderocol-resistant Acinetobacter baumannii during an outbreak in the burn intensive care unit","volume":"76","author":"Smoke","year":"2023","journal-title":"Clin. Infect. Dis."},{"key":"ref116","doi-asserted-by":"publisher","first-page":"5359","DOI":"10.1128\/JB.182.19.5359-5364.2000","article-title":"Binding of ferric enterobactin by the escherichia coli periplasmic protein fepB","volume":"182","author":"Sprencel","year":"2000","journal-title":"J. Bacteriol."},{"key":"ref117","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/0378-1119(87)90365-9","article-title":"High-copy-number and low-copy-number plasmid vectors for lacZ\u03b1-complementation and chloramphenicol-or kanamycin-resistance selection","volume":"61","author":"Takeshita","year":"1987","journal-title":"Gene"},{"key":"ref118","doi-asserted-by":"publisher","first-page":"6689","DOI":"10.1128\/JB.180.24.6689-6696.1998","article-title":"Selectivity of ferric enterobactin binding and cooperativity of transport in gram-negative bacteria","volume":"180","author":"Thulasiraman","year":"1998","journal-title":"J. Bacteriol."},{"key":"ref119","doi-asserted-by":"publisher","first-page":"dlad078","DOI":"10.1093\/jacamr\/dlad078","article-title":"Salvage therapy with sulbactam\/durlobactam against cefiderocol-resistant Acinetobacter baumannii in a critically ill burn patient: clinical challenges and molecular characterization","volume":"5","author":"Tiseo","year":"2023","journal-title":"JAC Antimicrob. Resist."},{"key":"ref120","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref121","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1128\/jb.126.1.7-12.1976","article-title":"Siderophore protection against colicins M, B, V, and Ia in Escherichia coli","volume":"126","author":"Wayne","year":"1976","journal-title":"J. Bacteriol."},{"key":"ref122","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1128\/jb.121.2.497-503.1975","article-title":"Evidence for common binding sites for ferrichrome compounds and bacteriophage phi 80 in the cell envelope of Escherichia coli","volume":"121","author":"Wayne","year":"1975","journal-title":"J. Bacteriol."},{"key":"ref123","doi-asserted-by":"publisher","first-page":"473","DOI":"10.410.1021\/bc300610f","article-title":"Trihydroxamate siderophore-fluoroquinolone conjugates are selective sideromycin antibiotics that target Staphylococcus aureus","volume":"24","author":"Wencewicz","year":"2013","journal-title":"Bioconjug. Chem."},{"key":"ref124","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s40121-020-00286-6","article-title":"Cefiderocol: A novel agent for the management of multidrug-resistant gram-negative organisms","volume":"9","author":"Wu","year":"2020","journal-title":"Infect. Dis. Ther."},{"key":"ref125","doi-asserted-by":"publisher","first-page":"S544","DOI":"10.1093\/cid\/ciz827","article-title":"In vitro activity of Cefiderocol against a broad range of clinically important gram-negative Bacteria","volume":"69","author":"Yamano","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref126","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1007\/s40265-019-1055-2","article-title":"Cefiderocol: A Siderophore cephalosporin with activity against Carbapenem-resistant and multidrug-resistant gram-negative Bacilli","volume":"79","author":"Zhanel","year":"2019","journal-title":"Drugs"},{"key":"ref127","doi-asserted-by":"publisher","first-page":"2363","DOI":"10.1099\/mic.0.27888-0","article-title":"Functions of the siderophore esterases IroD and IroE in iron-salmochelin utilization","volume":"151","author":"Zhu","year":"2005","journal-title":"Microbiology (Reading)"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2024.1355253\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T14:15:14Z","timestamp":1711548914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2024.1355253\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,27]]},"references-count":127,"alternative-id":["10.3389\/fmicb.2024.1355253"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2024.1355253","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,27]]},"article-number":"1355253"}}