{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T04:53:28Z","timestamp":1794027208861,"version":"4.8.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-17044-8","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T19:18:48Z","timestamp":1756149528000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Exploring mutational possibilities of KPC variants to reach high level resistance to cefiderocol"],"prefix":"10.1038","volume":"15","author":[{"given":"Sidonie","family":"Hanna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"La","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Yoshii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maud","family":"Gits-Muselli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imane","family":"El Meouche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"Benhadid-brahmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Bonacorsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Birgy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"17044_CR1","doi-asserted-by":"publisher","first-page":"S28","DOI":"10.1093\/infdis\/jiw282","volume":"215","author":"LK Logan","year":"2017","unstructured":"Logan, L. K. & Weinstein, R. A. The epidemiology of carbapenem-resistant enterobacteriaceae: The impact and evolution of a global menace. J. Infect. Dis. 215, S28\u2013S36 (2017).","journal-title":"J. Infect. Dis."},{"key":"17044_CR2","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.3389\/fmicb.2019.01823","volume":"10","author":"X Cui","year":"2019","unstructured":"Cui, X., Zhang, H. & Du, H. Carbapenemases in enterobacteriaceae: detection and antimicrobial therapy. Front. Microbiol. 10, 1823 (2019).","journal-title":"Front. Microbiol."},{"key":"17044_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2023.106090","volume":"179","author":"T Karampatakis","year":"2023","unstructured":"Karampatakis, T., Tsergouli, K. & Lowrie, K. Efficacy and safety of ceftazidime-avibactam compared to other antimicrobials for the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae strains, a systematic review and meta-analysis. Microb. Pathog. 179, 106090 (2023).","journal-title":"Microb. Pathog."},{"key":"17044_CR4","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s40265-017-0851-9","volume":"78","author":"GG Zhanel","year":"2018","unstructured":"Zhanel, G. G. et al. Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-\u03b2-lactamase inhibitor combinations. Drugs 78, 65\u201398 (2018).","journal-title":"Drugs"},{"key":"17044_CR5","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s40265-013-0013-7","volume":"73","author":"GG Zhanel","year":"2013","unstructured":"Zhanel, G. G. et al. Ceftazidime-avibactam: a novel cephalosporin\/\u03b2-lactamase inhibitor combination. Drugs 73, 159\u2013177 (2013).","journal-title":"Drugs"},{"key":"17044_CR6","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00447-22","volume":"66","author":"CA Hobson","year":"2022","unstructured":"Hobson, C. A. et al. Klebsiella pneumoniae carbapenemase variants resistant to ceftazidime-avibactam: An evolutionary overview. Antimicrob. Agents Chemother. 66, e0044722 (2022).","journal-title":"Antimicrob. Agents Chemother."},{"key":"17044_CR7","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00008-23","volume":"36","author":"L Ding","year":"2023","unstructured":"Ding, L. et al. Klebsiella pneumoniae carbapenemase variants: the new threat to global public health. Clin. Microbiol. Rev. 36, e0000823 (2023).","journal-title":"Clin. Microbiol. Rev."},{"key":"17044_CR8","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.cmi.2021.11.025","volume":"28","author":"M Paul","year":"2022","unstructured":"Paul, M. et al. European society of clinical microbiology and infectious diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin. Microbiol. Infect. 28, 521\u2013547 (2022).","journal-title":"Clin. Microbiol. Infect."},{"key":"17044_CR9","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1093\/cid\/ciac268","volume":"75","author":"PD Tamma","year":"2022","unstructured":"Tamma, P. D. et al. Infectious diseases society of America 2022 guidance on the treatment of extended-spectrum \u03b2-lactamase producing enterobacterales (ESBL-E), carbapenem-resistant enterobacterales (CRE), and pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin. Infect. Dis. 75, 187\u2013212 (2022).","journal-title":"Clin. Infect. Dis."},{"key":"17044_CR10","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.jgar.2022.06.021","volume":"30","author":"P Gaibani","year":"2022","unstructured":"Gaibani, P., Amadesi, S., Lazzarotto, T. & Ambretti, S. Genome characterization of a Klebsiella pneumoniae co-producing OXA-181 and KPC-121 resistant to ceftazidime\/avibactam, meropenem\/vaborbactam, imipenem\/relebactam and cefiderocol isolated from a critically ill patient. J. Glob. Antimicrob. Resist. 30, 262\u2013264 (2022).","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"17044_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2023.106935","volume":"62","author":"E Gato","year":"2023","unstructured":"Gato, E. et al. In vitro development of imipenem\/relebactam resistance in KPC-producing Klebsiella pneumoniae involves multiple mutations including OmpK36 disruption and KPC modification. Int. J. Antimicrob. Agents 62, 106935 (2023).","journal-title":"Int. J. Antimicrob. Agents"},{"key":"17044_CR12","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.cmi.2022.01.025","volume":"28","author":"D Lombardo","year":"2022","unstructured":"Lombardo, D., Ambretti, S., Lazzarotto, T. & Gaibani, P. In vitro activity of imipenem-relebactam against KPC-producing Klebsiella pneumoniae resistant to ceftazidime-avibactam and\/or meropenem-vaborbactam. Clin. Microbiol. Infect. 28, 749\u2013751 (2022).","journal-title":"Clin. Microbiol. Infect."},{"key":"17044_CR13","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1177\/1060028020929988","volume":"54","author":"RM El-Lababidi","year":"2020","unstructured":"El-Lababidi, R. M. & Rizk, J. G. Cefiderocol: A siderophore cephalosporin. Ann. Pharmacother. 54, 1215\u20131231 (2020).","journal-title":"Ann. Pharmacother."},{"key":"17044_CR14","doi-asserted-by":"publisher","first-page":"S538","DOI":"10.1093\/cid\/ciz826","volume":"69","author":"T Sato","year":"2019","unstructured":"Sato, T. & Yamawaki, K. Cefiderocol: Discovery, chemistry, and in vivo profiles of a novel siderophore cephalosporin. Clin. Infect. Dis. 69, S538\u2013S543 (2019).","journal-title":"Clin. Infect. Dis."},{"key":"17044_CR15","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/j.ejmech.2018.06.014","volume":"155","author":"T Aoki","year":"2018","unstructured":"Aoki, T. et al. Cefiderocol (S-649266), A new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other gram-negative pathogens including multi-drug resistant bacteria: Structure activity relationship. Eur. J. Med. Chem. 155, 847\u2013868 (2018).","journal-title":"Eur. J. Med. Chem."},{"key":"17044_CR16","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1093\/jac\/dkad004","volume":"78","author":"AB Jousset","year":"2023","unstructured":"Jousset, A. B. et al. Rapid selection of a cefiderocol-resistant Escherichia coli producing NDM-5 associated with a single amino acid substitution in the CirA siderophore receptor. J. Antimicrob. Chemother. 78, 1125\u20131127 (2023).","journal-title":"J. Antimicrob. Chemother."},{"key":"17044_CR17","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1007\/s10096-021-04397-x","volume":"41","author":"L Poirel","year":"2022","unstructured":"Poirel, L., Sadek, M., Kusaksizoglu, A. & Nordmann, P. Co-resistance to ceftazidime-avibactam and cefiderocol in clinical isolates producing KPC variants. Eur. J. Clin. Microbiol. Infect. Dis. 41, 677\u2013680 (2022).","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"issue":"1172","key":"17044_CR18","first-page":"e7","volume":"27","author":"CA Hobson","year":"2021","unstructured":"Hobson, C. A. et al. Cross-resistance to cefiderocol and ceftazidime-avibactam in KPC \u03b2-lactamase mutants and the inoculum effect. Clin. Microbiol. Infect. 27(1172), e7-1172.e10 (2021).","journal-title":"Clin. Microbiol. Infect."},{"key":"17044_CR19","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1093\/jac\/dkad086","volume":"78","author":"JA Castillo-Polo","year":"2023","unstructured":"Castillo-Polo, J. A. et al. Outbreak by KPC-62-producing ST307 Klebsiella pneumoniae isolates resistant to ceftazidime\/avibactam and cefiderocol in a university hospital in Madrid Spain. J. Antimicrob. Chemother. 78, 1259\u20131264 (2023).","journal-title":"J. Antimicrob. Chemother."},{"key":"17044_CR20","doi-asserted-by":"publisher","first-page":"507","DOI":"10.3390\/pathogens13060507","volume":"13","author":"S Amadesi","year":"2024","unstructured":"Amadesi, S. et al. Complete Genome sequence of a klebsiella pneumoniae strain carrying novel variant blaKPC-203, Cross-resistant to ceftazidime\/avibactam and cefiderocol, but susceptible to carbapenems, isolated in Italy, 2023. Pathogens 13, 507 (2024).","journal-title":"Pathogens"},{"key":"17044_CR21","doi-asserted-by":"publisher","first-page":"507","DOI":"10.3390\/antibiotics13060507","volume":"13","author":"M Giufr\u00e8","year":"2024","unstructured":"Giufr\u00e8, M. et al. Detection of KPC-216, a novel KPC-3 variant, in a clinical isolate of Klebsiella pneumoniae ST101 Co-resistant to ceftazidime-avibactam and cefiderocol. Antibiotics 13, 507 (2024).","journal-title":"Antibiotics"},{"key":"17044_CR22","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01108-23","volume":"68","author":"A Birgy","year":"2024","unstructured":"Birgy, A., Nnabuife, C. & Palzkill, T. The mechanism of ceftazidime and cefiderocol hydrolysis by D179Y variants of KPC carbapenemases is similar and involves the formation of a long-lived covalent intermediate. Antimicrob. Agents Chemother. 68, e0110823 (2024).","journal-title":"Antimicrob. Agents Chemother."},{"key":"17044_CR23","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1111\/j.1574-6976.2010.00222.x","volume":"34","author":"MLM Salverda","year":"2010","unstructured":"Salverda, M. L. M., De Visser, J. A. G. M. & Barlow, M. Natural evolution of TEM-1 \u03b2-lactamase: Experimental reconstruction and clinical relevance. FEMS Microbiol. Rev. 34, 1015\u20131036 (2010).","journal-title":"FEMS Microbiol. Rev."},{"key":"17044_CR24","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.1093\/jac\/dkac221","volume":"77","author":"C Fr\u00f6hlich","year":"2022","unstructured":"Fr\u00f6hlich, C., S\u00f8rum, V., Tokuriki, N., Johnsen, P. J. & Samuelsen, \u00d8. Evolution of \u03b2-lactamase-mediated cefiderocol resistance. J. Antimicrob. Chemother. 77, 2429\u20132436 (2022).","journal-title":"J. Antimicrob. Chemother."},{"key":"17044_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2019.09.020","volume":"55","author":"P Gaibani","year":"2020","unstructured":"Gaibani, P., Ambretti, S., Campoli, C., Viale, P. & Re, M. C. Genomic characterization of a Klebsiella pneumoniae ST1519 resistant to ceftazidime\/avibactam carrying a novel KPC variant (KPC-36). Int. J. Antimicrob. Agents 55, 105816 (2020).","journal-title":"Int. J. Antimicrob. Agents"},{"key":"17044_CR26","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1093\/jac\/dkz026","volume":"74","author":"P Hemarajata","year":"2019","unstructured":"Hemarajata, P. & Humphries, R. M. Ceftazidime\/avibactam resistance associated with L169P mutation in the omega loop of KPC-2. J. Antimicrob. Chemother. 74, 1241\u20131243 (2019).","journal-title":"J. Antimicrob. Chemother."},{"key":"17044_CR27","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.jgar.2019.11.007","volume":"22","author":"\u00c1 Cano","year":"2020","unstructured":"Cano, \u00c1. et al. Use of carbapenems in the combined treatment of emerging ceftazidime\/avibactam-resistant and carbapenem-susceptible KPC-producing Klebsiella pneumoniae infections: Report of a case and review of the literature. J. Glob. Antimicrob. Resist. 22, 9\u201312 (2020).","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"17044_CR28","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1080\/14756366.2017.1344235","volume":"32","author":"T Naas","year":"2017","unstructured":"Naas, T. et al. Beta-lactamase database (BLDB)\u2014structure and function. J Enzyme Inhib Med Chem 32, 917\u2013919 (2017).","journal-title":"J Enzyme Inhib Med Chem"},{"key":"17044_CR29","unstructured":"European Committee on Antimicrobial Susceptibility Testing. Data from the EUCAST MIC distribution website, last accessed 26 Sept 2024. https:\/\/www.eucast.org (2024)."},{"key":"17044_CR30","doi-asserted-by":"publisher","first-page":"e01454","DOI":"10.1128\/AAC.01454-17","volume":"62","author":"A Ito","year":"2018","unstructured":"Ito, A. et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against gram-negative bacteria. Antimicrob. Agents Chemother. 62, e01454-e1517 (2018).","journal-title":"Antimicrob. Agents Chemother."},{"key":"17044_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/s41429-024-00762-y","author":"R Kriz","year":"2024","unstructured":"Kriz, R. et al. In vitro resistance development gives insights into molecular resistance mechanisms against cefiderocol. J. Antibiot. https:\/\/doi.org\/10.1038\/s41429-024-00762-y (2024).","journal-title":"J. Antibiot."},{"key":"17044_CR32","first-page":"e02670","volume":"10","author":"Q Wang","year":"2022","unstructured":"Wang, Q. et al. Occurrence of high levels of cefiderocol resistance in carbapenem-resistant escherichia coli before its approval in China: A report from China CRE-network. Microbiol. Spectr. 10, e02670-e2721 (2022).","journal-title":"Microbiol. Spectr."},{"key":"17044_CR33","doi-asserted-by":"publisher","first-page":"4910","DOI":"10.1038\/ncomms5910","volume":"5","author":"SW Seo","year":"2014","unstructured":"Seo, S. W. et al. Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli. Nat. Commun. 5, 4910 (2014).","journal-title":"Nat. Commun."},{"key":"17044_CR34","doi-asserted-by":"publisher","first-page":"29478","DOI":"10.1074\/jbc.M303381200","volume":"278","author":"JP McHugh","year":"2003","unstructured":"McHugh, J. P. et al. Global iron-dependent gene regulation in Escherichia coli. A new mechanism for iron homeostasis. J. Biol. Chem. 278, 29478\u201329486 (2003).","journal-title":"J. Biol. Chem."},{"key":"17044_CR35","doi-asserted-by":"publisher","first-page":"6334","DOI":"10.1128\/AAC.01345-12","volume":"56","author":"CJ McPherson","year":"2012","unstructured":"McPherson, C. J. et al. Clinically relevant Gram-negative resistance mechanisms have no effect on the efficacy of MC-1, a novel siderophore-conjugated monocarbam. Antimicrob. Agents Chemother. 56, 6334\u20136342 (2012).","journal-title":"Antimicrob. Agents Chemother."},{"key":"17044_CR36","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s41598-020-57505-w","volume":"10","author":"CA Hobson","year":"2020","unstructured":"Hobson, C. A. et al. Impact of anticancer chemotherapy on the extension of beta-lactamase spectrum: an example with KPC-type carbapenemase activity towards ceftazidime-avibactam. Sci. Rep. 10, 589 (2020).","journal-title":"Sci. Rep."},{"key":"17044_CR37","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1038\/msb4100050","volume":"2","author":"T Baba","year":"2006","unstructured":"Baba, T. et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: The Keio collection. Mol. Syst. Biol. 2, 2006\u20130008 (2006).","journal-title":"Mol. Syst. Biol."},{"key":"17044_CR38","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/0378-1119(95)00193-A","volume":"158","author":"PP Cherepanov","year":"1995","unstructured":"Cherepanov, P. P. & Wackernagel, W. Gene disruption in Escherichia coli: TcR and KmR cassettes with the option of Flp-catalyzed excision of the antibiotic-resistance determinant. Gene 158, 9\u201314 (1995).","journal-title":"Gene"},{"key":"17044_CR39","doi-asserted-by":"publisher","first-page":"E97","DOI":"10.1093\/nar\/28.22.e97","volume":"28","author":"MK Chaveroche","year":"2000","unstructured":"Chaveroche, M. K., Ghigo, J. M. & d\u2019Enfert, C. A rapid method for efficient gene replacement in the filamentous fungus Aspergillus nidulans. Nucleic Acids Res. 28, E97 (2000).","journal-title":"Nucleic Acids Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-17044-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-17044-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-17044-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T22:59:50Z","timestamp":1757458790000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-17044-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,25]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["17044"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-17044-8","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.02.14.638246","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,25]]},"assertion":[{"value":"26 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"31312"}}