{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T03:48:11Z","timestamp":1782445691977,"version":"3.54.5"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Antibiot"],"published-print":{"date-parts":[[2022,2]]},"DOI":"10.1038\/s41429-021-00486-3","type":"journal-article","created":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T15:03:01Z","timestamp":1637938981000},"page":"98-107","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae"],"prefix":"10.1038","volume":"75","author":[{"given":"Kiyoko","family":"Fujita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iichiro","family":"Takata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ippei","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotoshi","family":"Okumura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsumasa","family":"Otake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Takashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0720-3906","authenticated-orcid":false,"given":"Hiroyuki","family":"Sugiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,26]]},"reference":[{"key":"486_CR1","doi-asserted-by":"publisher","first-page":"e969","DOI":"10.1016\/S2214-109X(18)30278-X","volume":"6","author":"E Temkin","year":"2018","unstructured":"Temkin E, Fallach N, Almagor J, Gladstone BP, Tacconelli E, Carmeli Y. Estimating the number of infections caused by antibiotic-resistant Escherichia coli and Klebsiella pneumoniae in 2014: a modelling study. Lancet Glob Health. 2018;6:e969\u2013e979. https:\/\/doi.org\/10.1016\/S2214-109X(18)30278-X.","journal-title":"Lancet Glob Health"},{"key":"486_CR2","doi-asserted-by":"publisher","first-page":"19858","DOI":"10.1016\/S0021-9258(19)36592-5","volume":"268","author":"MS Anderson","year":"1993","unstructured":"Anderson MS, Bull HG, Galloway SM, Kelly TM, Mohan S, Radika K, et al. UDP-N-acetylglucosamine acyltransferase of Escherichia coli. The first step of endotoxin biosynthesis is thermodynamically unfavorable. J Biol Chem. 1993;268:19858\u201365.","journal-title":"J Biol Chem"},{"key":"486_CR3","doi-asserted-by":"publisher","unstructured":"Lin L, Tan B, Pantapalangkoor P, Ho T, Baquir B, Tomaras A, et al. Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. mBio. 2012, 3. https:\/\/doi.org\/10.1128\/mBio.00312-12.","DOI":"10.1128\/mBio.00312-12."},{"key":"486_CR4","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1002\/cmdc.201900287","volume":"14","author":"F Cohen","year":"2019","unstructured":"Cohen F, Aggen JB, Andrews LD, Assar Z, Boggs J, Choi T, et al. Optimization of LpxC inhibitors for antibacterial activity and cardiovascular safety. ChemMedChem 2019;14:1560\u201372.","journal-title":"ChemMedChem"},{"key":"486_CR5","doi-asserted-by":"publisher","first-page":"2874","DOI":"10.1093\/jac\/dkw210","volume":"71","author":"M Titecat","year":"2016","unstructured":"Titecat M, Liang X, Lee CJ, Charlet A, Hocquet D, Lambert T, et al. High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors. J Antimicrob Chemother. 2016;71:2874\u201382.","journal-title":"J Antimicrob Chemother"},{"key":"486_CR6","doi-asserted-by":"publisher","first-page":"5002","DOI":"10.1021\/acs.jmedchem.7b00377","volume":"60","author":"G Piizzi","year":"2017","unstructured":"Piizzi G, Parker DT, Peng Y, Dobler M, Patnaik A, Wattanasin S, et al. Design, synthesis, and properties of a potent inhibitor of Pseudomonas aeruginosa deacetylase LpxC. J Med Chem. 2017;60:5002\u201314.","journal-title":"J Med Chem"},{"key":"486_CR7","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.2174\/0929867023369402","volume":"9","author":"EMF Muri","year":"2002","unstructured":"Muri EMF, Nieto MJ, Sindelar RD, Williamson JS. Hydroxamic acids as pharmacological agents. Curr Med Chem. 2002;9:1631\u201353.","journal-title":"Curr Med Chem"},{"key":"486_CR8","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/cmdc.201500486","volume":"11","author":"S Shen","year":"2016","unstructured":"Shen S, Kozikowski AP. Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors\u2212What Some May Have Forgotten or Would Rather Forget? ChemMedChem 2016;11:15\u201321.","journal-title":"ChemMedChem"},{"key":"486_CR9","doi-asserted-by":"publisher","first-page":"115826","DOI":"10.1016\/j.bmc.2020.115826.","volume":"28","author":"T Furuya","year":"2020","unstructured":"Furuya T, Shapiro AB, Comita-Prevoir J, Kuenstner EJ, Zhang J, Ribe SD, et al. N-Hydroxyformamide LpxC inhibitors, their in vivo efficacy in a mouse Escherichia coli infection model, and their safety in a rat hemodynamic assay. Bioorg Med Chem. 2020;28:115826. https:\/\/doi.org\/10.1016\/j.bmc.2020.115826.","journal-title":"Bioorg Med Chem"},{"key":"486_CR10","doi-asserted-by":"publisher","first-page":"115964","DOI":"10.1016\/j.bmc.2020.115964.","volume":"30","author":"F Ushiyama","year":"2021","unstructured":"Ushiyama F, Takashima H, Matsuda Y, Ogata Y, Sasamoto N, Kurimoto-Tsuruta R, et al. Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC Inhibitors: Discovery of TP0586532. Bioorg Med Chem. 2021;30:115964. https:\/\/doi.org\/10.1016\/j.bmc.2020.115964.","journal-title":"Bioorg Med Chem"},{"key":"486_CR11","unstructured":"Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; informational supplement. CLSI document M100-S29. Clinical and Laboratory Standards Institute, Wayne, PA. 2019."},{"key":"486_CR12","doi-asserted-by":"publisher","first-page":"14805","DOI":"10.1021\/acs.jmedchem.0c01215","volume":"63","author":"Y Yamada","year":"2020","unstructured":"Yamada Y, Takashima H, Walmsley DL, Ushiyama F, Matsuda Y, Kanazawa H, et al. Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity. J Med Chem. 2020;63:14805\u201320.","journal-title":"J Med Chem"},{"key":"486_CR13","unstructured":"The European Committee on Antimicrobial Susceptibility Testing. Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 6.0. 2016."},{"key":"486_CR14","doi-asserted-by":"publisher","first-page":"4534","DOI":"10.1128\/iai.62.10.4534-4541.1994","volume":"62","author":"N Tsuchimori","year":"1994","unstructured":"Tsuchimori N, Hayashi R, Shino A, Yamazaki T, Okonogi K. Enterococcus faecalis aggravates pyelonephritis caused by Pseudomonas aeruginosa in experimental ascending mixed urinary tract infection in mice. Infect Immun. 1994;62:4534\u201341.","journal-title":"Infect Immun"},{"key":"486_CR15","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1021\/ml500210x","volume":"5","author":"KE Murphy-Benenato","year":"2014","unstructured":"Murphy-Benenato KE, Olivier N, Choy A, Ross PL, Miller MD, Thresher J, et al. Synthesis, structure, and SAR of Tetrahydropyran-based LpxC inhibitors. ACS Med Chem Lett. 2014;5:1213\u20138.","journal-title":"ACS Med Chem Lett"},{"key":"486_CR16","unstructured":"Global antimicrobial resistance and use surveillance system (GLASS) report 2021. Geneva: World Health Organization; 2021."},{"key":"486_CR17","doi-asserted-by":"publisher","first-page":"a025304","DOI":"10.1101\/cshperspect.a025304","volume":"6","author":"AL Erwin","year":"2016","unstructured":"Erwin AL. Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC. Cold Spring Harb Perspect Med. 2016;6:a025304.","journal-title":"Cold Spring Harb Perspect Med"},{"key":"486_CR18","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.ijantimicag.2015.07.017","volume":"46","author":"M Garc\u00eda-Quintanilla","year":"2015","unstructured":"Garc\u00eda-Quintanilla M, Carretero-Ledesma M, Moreno-Mart\u00ednez P, Mart\u00edn-Pe\u00f1a R, Pach\u00f3n J, McConnell MJ. Lipopolysaccharide loss produces partial colistin dependence and collateral sensitivity to azithromycin, rifampicin and vancomycin in Acinetobacter baumannii. Int J Antimicrob Agents. 2015;46:696\u2013702.","journal-title":"Int J Antimicrob Agents"},{"key":"486_CR19","first-page":"e01951","volume":"64","author":"M Castanheira","year":"2020","unstructured":"Castanheira M, Doyle TB, Kantro V, Mendes RE, Shortridge D. Meropenem-Vaborbactam Activity against Carbapenem-Resistant Enterobacterales Isolates Collected in U.S. Hospitals during 2016 to 2018. Antimicrob Agents Chemother. 2020;64:e01951\u201319.","journal-title":"Antimicrob Agents Chemother"},{"key":"486_CR20","unstructured":"Japan Nosocomial Infections Surveillance report. 2020. https:\/\/janis.mhlw.go.jp\/report\/open_report\/2020\/3\/1\/ken_Open_Report_202000.pdf."},{"key":"486_CR21","first-page":"245","volume":"30","author":"T Yagi","year":"2020","unstructured":"Yagi T. Infection Prevention and Control Measures for Controlling Carbapenem-Resistant Enterobacteriaceae\/carbapenemase-producing Enterobacteriaceae. J Jpn Soc Clin Microbiol. 2020;30:245\u201352.","journal-title":"J Jpn Soc Clin Microbiol"},{"key":"486_CR22","doi-asserted-by":"publisher","first-page":"6605","DOI":"10.1128\/AAC.01165-15","volume":"59","author":"RM Humphries","year":"2015","unstructured":"Humphries RM, Yang S, Hemarajata P, Ward KW, Hindler JA, Miller SA, et al. First report of ceftazidime-avibactam resistance in a KPC-3-expressing Klebsiella pneumoniae isolate. Antimicrob Agents Chemother. 2015;59:6605\u20137.","journal-title":"Antimicrob Agents Chemother"},{"key":"486_CR23","doi-asserted-by":"publisher","first-page":"5475","DOI":"10.1074\/jbc.M112.447607","volume":"288","author":"D Zeng","year":"2013","unstructured":"Zeng D, Zhao J, Chung HS, Guan Z, Raetz CR, Zhou P. Mutants resistant to LpxC inhibitors by rebalancing cellular homeostasis. J Biol Chem. 2013;288:5475\u201386.","journal-title":"J Biol Chem"},{"key":"486_CR24","doi-asserted-by":"publisher","first-page":"32896","DOI":"10.1016\/S0021-9258(20)30075-2","volume":"269","author":"S Mohan","year":"1994","unstructured":"Mohan S, Kelly TM, Eveland SS, Raetz CR, Anderson MS. An Escherichia coli Gene (FabZ) Encoding (3R)-Hydroxymyristoyl Acyl Carrier Protein Dehydrase. J Biol Chem. 1994;269:32896\u2013903.","journal-title":"J Biol Chem"},{"key":"486_CR25","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1128\/AAC.46.6.1793-1799.2002","volume":"46","author":"JM Clements","year":"2002","unstructured":"Clements JM, Coignard F, Johnson I, Chandler S, Palan S, Waller A, et al. Antibacterial activities and characterization of novel inhibitors of LpxC. Antimicrob Agents Chemother. 2002;46:1793\u20139.","journal-title":"Antimicrob Agents Chemother"},{"key":"486_CR26","doi-asserted-by":"publisher","first-page":"e00508","DOI":"10.1128\/mSphere.00508-18","volume":"3","author":"M Mostafavi","year":"2018","unstructured":"Mostafavi M, Wang L, Xie L, Takeoka KT, Richie DL, Casey F, et al. Interplay of Klebsiella pneumoniae fabZ and lpxC mutations leads to LpxC inhibitor-dependent growth resulting from loss of membrane homeostasis. mSphere 2018;3:e00508\u201318.","journal-title":"mSphere"},{"key":"486_CR27","doi-asserted-by":"crossref","unstructured":"Tomaras AP, McPherson CJ, Kuhn M, Carifa A, Mullins L, George D, et al. LpxC inhibitors as new antibacterial agents and tools for studying regulation of lipid A biosynthesis in Gram-negative pathogens. 2014;mBio 5:e01551-14.","DOI":"10.1128\/mBio.01551-14"}],"container-title":["The Journal of Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41429-021-00486-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41429-021-00486-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41429-021-00486-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T11:04:22Z","timestamp":1643022262000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41429-021-00486-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,26]]},"references-count":27,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["486"],"URL":"https:\/\/doi.org\/10.1038\/s41429-021-00486-3","relation":{},"ISSN":["0021-8820","1881-1469"],"issn-type":[{"value":"0021-8820","type":"print"},{"value":"1881-1469","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,26]]},"assertion":[{"value":"12 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 October 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}