{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T21:16:47Z","timestamp":1793654207912,"version":"4.5.1"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"7894","license":[{"start":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T00:00:00Z","timestamp":1641340800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T00:00:00Z","timestamp":1641340800000},"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":["Nature"],"published-print":{"date-parts":[[2022,1,27]]},"DOI":"10.1038\/s41586-021-04264-x","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T13:09:16Z","timestamp":1641388156000},"page":"606-611","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":220,"title":["A naturally inspired antibiotic to target multidrug-resistant pathogens"],"prefix":"10.1038","volume":"601","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7121-0396","authenticated-orcid":false,"given":"Zongqiang","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1806-7935","authenticated-orcid":false,"given":"Bimal","family":"Koirala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3349-8856","authenticated-orcid":false,"given":"Yozen","family":"Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Zimmerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Perlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5967-8586","authenticated-orcid":false,"given":"Sean F.","family":"Brady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,5]]},"reference":[{"key":"4264_CR1","first-page":"277","volume":"40","author":"CL Ventola","year":"2015","unstructured":"Ventola, C. L. The antibiotic resistance crisis: part 1: causes and threats. P. T. 40, 277\u2013283 (2015).","journal-title":"P. T."},{"key":"4264_CR2","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/nrd2201","volume":"6","author":"DJ Payne","year":"2007","unstructured":"Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov. 6, 29\u201340 (2007).","journal-title":"Nat. Rev. Drug Discov."},{"key":"4264_CR3","doi-asserted-by":"publisher","first-page":"e02442","DOI":"10.1128\/AAC.02442-17","volume":"62","author":"D Deveson Lucas","year":"2018","unstructured":"Deveson Lucas, D. et al. Emergence of high-level colistin resistance in an Acinetobacter baumannii clinical isolate mediated by inactivation of the global regulator H-NS. Antimicrob. Agents Chemother. 62, e02442-17 (2018).","journal-title":"Antimicrob. Agents Chemother."},{"key":"4264_CR4","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1007\/s00284-021-02353-8","volume":"78","author":"GL Aitolo","year":"2021","unstructured":"Aitolo, G. L., Adeyemi, O. S., Afolabi, B. L. & Owolabi, A. O. Neisseria gonorrhoeae antimicrobial resistance: past to present to future. Curr. Microbiol. 78, 867\u2013878 (2021).","journal-title":"Curr. Microbiol."},{"key":"4264_CR5","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/S1473-3099(17)30753-3","volume":"18","author":"E Tacconelli","year":"2018","unstructured":"Tacconelli, E. et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 18, 318\u2013327 (2018).","journal-title":"Lancet Infect. Dis."},{"key":"4264_CR6","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/s41586-019-1791-1","volume":"576","author":"Y Imai","year":"2019","unstructured":"Imai, Y. et al. A new antibiotic selectively kills Gram-negative pathogens. Nature 576, 459\u2013464 (2019).","journal-title":"Nature"},{"key":"4264_CR7","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1586\/eri.12.78","volume":"10","author":"S Biswas","year":"2012","unstructured":"Biswas, S., Brunel, J. M., Dubus, J. C., Reynaud-Gaubert, M. & Rolain, J. M. Colistin: an update on the antibiotic of the 21st century. Expert Rev. Anti Infect. Ther. 10, 917\u2013934 (2012).","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"4264_CR8","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/S1473-3099(15)00424-7","volume":"16","author":"YY Liu","year":"2016","unstructured":"Liu, Y. Y. et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect. Dis. 16, 161\u2013168 (2016).","journal-title":"Lancet Infect. Dis."},{"key":"4264_CR9","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.ijantimicag.2016.11.029","volume":"49","author":"K Jeannot","year":"2017","unstructured":"Jeannot, K., Bolard, A. & Plesiat, P. Resistance to polymyxins in Gram-negative organisms. Int. J. Antimicrob. Agents 49, 526\u2013535 (2017).","journal-title":"Int. J. Antimicrob. Agents"},{"key":"4264_CR10","first-page":"e00580","volume":"61","author":"YY Liu","year":"2017","unstructured":"Liu, Y. Y. et al. Structural modification of lipopolysaccharide conferred by mcr-1 in Gram-negative ESKAPE pathogens. Antimicrob. Agents Chemother. 61, e00580-17 (2017).","journal-title":"Antimicrob. Agents Chemother"},{"key":"4264_CR11","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1093\/jac\/dkw274","volume":"71","author":"S Schwarz","year":"2016","unstructured":"Schwarz, S. & Johnson, A. P. Transferable resistance to colistin: a new but old threat. J. Antimicrob. Chemother. 71, 2066\u20132070 (2016).","journal-title":"J. Antimicrob. Chemother."},{"key":"4264_CR12","doi-asserted-by":"publisher","first-page":"e20190237","DOI":"10.1590\/0037-8682-0237-2019","volume":"52","author":"F Hameed","year":"2019","unstructured":"Hameed, F. et al. Plasmid-mediated mcr-1 gene in Acinetobacter baumannii and Pseudomonas aeruginosa: first report from Pakistan. Rev. Soc. Bras. Med. Trop. 52, e20190237 (2019).","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"4264_CR13","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S1473-3099(17)30266-9","volume":"17","author":"GB Tian","year":"2017","unstructured":"Tian, G. B. et al. MCR-1-producing Klebsiella pneumoniae outbreak in China. Lancet Infect. Dis. 17, 577 (2017).","journal-title":"Lancet Infect. Dis."},{"key":"4264_CR14","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1038\/nrmicro3496","volume":"13","author":"PJ Rutledge","year":"2015","unstructured":"Rutledge, P. J. & Challis, G. L. Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nat. Rev. Microbiol. 13, 509\u2013523 (2015).","journal-title":"Nat. Rev. Microbiol."},{"key":"4264_CR15","doi-asserted-by":"publisher","first-page":"3770","DOI":"10.1002\/anie.201609079","volume":"56","author":"RD Sussmuth","year":"2017","unstructured":"Sussmuth, R. D. & Mainz, A. Nonribosomal peptide synthesis \u2013 principles and prospects. Angew. Chem. Int. Ed. Engl. 56, 3770\u20133821 (2017).","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"4264_CR16","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/S1074-5521(99)80082-9","volume":"6","author":"T Stachelhaus","year":"1999","unstructured":"Stachelhaus, T., Mootz, H. D. & Marahiel, M. A. The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases. Chem. Biol. 6, 493\u2013505 (1999).","journal-title":"Chem. Biol."},{"key":"4264_CR17","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1039\/C7NP00023E","volume":"34","author":"F Rabanal","year":"2017","unstructured":"Rabanal, F. & Cajal, Y. Recent advances and perspectives in the design and development of polymyxins. Nat. Prod. Rep. 34, 886\u2013908 (2017).","journal-title":"Nat. Prod. Rep."},{"key":"4264_CR18","doi-asserted-by":"crossref","unstructured":"Li, J., Nation, R. & Kaye, K. (eds) Polymyxin Antibiotics: From Laboratory Bench to Bedside Preface 1145, V\u2013VI (Springer, 2019).","DOI":"10.1007\/978-3-030-16373-0"},{"key":"4264_CR19","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1007\/s10295-019-02198-y","volume":"46","author":"HA Tomm","year":"2019","unstructured":"Tomm, H. A., Ucciferri, L. & Ross, A. C. Advances in microbial culturing conditions to activate silent biosynthetic gene clusters for novel metabolite production. J. Ind. Microbiol. Biotechnol. 46, 1381\u20131400 (2019).","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"4264_CR20","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1038\/nchembio.2207","volume":"12","author":"J Chu","year":"2016","unstructured":"Chu, J. et al. Discovery of MRSA active antibiotics using primary sequence from the human microbiome. Nat. Chem. Biol. 12, 1004\u20131006 (2016).","journal-title":"Nat. Chem. Biol."},{"key":"4264_CR21","doi-asserted-by":"publisher","first-page":"15737","DOI":"10.1021\/jacs.9b07317","volume":"141","author":"J Chu","year":"2019","unstructured":"Chu, J., Vila-Farres, X. & Brady, S. F. Bioactive synthetic-bioinformatic natural product cyclic peptides inspired by nonribosomal peptide synthetase gene clusters from the human microbiome. J. Am. Chem. Soc. 141, 15737\u201315741 (2019).","journal-title":"J. Am. Chem. Soc."},{"key":"4264_CR22","doi-asserted-by":"publisher","first-page":"14158","DOI":"10.1021\/jacs.0c04376","volume":"142","author":"J Chu","year":"2020","unstructured":"Chu, J. et al. Synthetic-bioinformatic natural product antibiotics with diverse modes of action. J. Am. Chem. Soc. 142, 14158\u201314168 (2020).","journal-title":"J. Am. Chem. Soc."},{"key":"4264_CR23","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1111\/mmi.14240","volume":"111","author":"KN Kang","year":"2019","unstructured":"Kang, K. N. et al. Colistin heteroresistance in Enterobacter cloacae is regulated by PhoPQ-dependent 4-amino-4-deoxy-l-arabinose addition to lipid A. Mol. Microbiol. 111, 1604\u20131616 (2019).","journal-title":"Mol. Microbiol."},{"key":"4264_CR24","doi-asserted-by":"publisher","first-page":"16574","DOI":"10.1021\/bi0518186","volume":"44","author":"AL McClerren","year":"2005","unstructured":"McClerren, A. L. et al. A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic activity comparable to ciprofloxacin. Biochemistry 44, 16574\u201316583 (2005).","journal-title":"Biochemistry"},{"key":"4264_CR25","doi-asserted-by":"publisher","first-page":"4971","DOI":"10.1128\/AAC.00834-10","volume":"54","author":"JH Moffatt","year":"2010","unstructured":"Moffatt, J. H. et al. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob. Agents Chemother. 54, 4971\u20134977 (2010).","journal-title":"Antimicrob. Agents Chemother."},{"key":"4264_CR26","doi-asserted-by":"publisher","first-page":"e00199","DOI":"10.1128\/mSphere.00199-17","volume":"2","author":"J-R Wei","year":"2017","unstructured":"Wei, J.-R. et al. LpxK is essential for growth of Acinetobacter baumannii ATCC 19606: relationship to toxic accumulation of lipid A pathway intermediates. mSphere 2, e00199\u201300117 (2017).","journal-title":"mSphere"},{"key":"4264_CR27","doi-asserted-by":"publisher","first-page":"e0160918","DOI":"10.1371\/journal.pone.0160918","volume":"11","author":"DL Richie","year":"2016","unstructured":"Richie, D. L. et al. Toxic accumulation of LPS pathway intermediates underlies the requirement of LpxH for growth of Acinetobacter baumannii ATCC 19606. PLoS ONE 11, e0160918 (2016).","journal-title":"PLoS ONE"},{"key":"4264_CR28","unstructured":"US Department of Health and Human Services. Antibiotic Resistance Threats in the United States; https:\/\/www.cdc.gov\/drugresistance\/pdf\/threats-report\/2019-ar-threats-report-508.pdf (2019)."},{"key":"4264_CR29","doi-asserted-by":"publisher","first-page":"3087","DOI":"10.1093\/jac\/dkaa205","volume":"75","author":"Z Ling","year":"2020","unstructured":"Ling, Z. et al. Epidemiology of mobile colistin resistance genes mcr-1 to mcr-9. J. Antimicrob. Chemother. 75, 3087\u20133095 (2020).","journal-title":"J. Antimicrob. Chemother."},{"key":"4264_CR30","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1246\/bcsj.77.1915","volume":"77","author":"N Sakura","year":"2004","unstructured":"Sakura, N. et al. The contribution of the N-terminal structure of polymyxin B peptides to antimicrobial and lipopolysaccharide binding activity. Bull. Chem. Soc. Jpn 77, 1915\u20131924 (2004).","journal-title":"Bull. Chem. Soc. Jpn"},{"key":"4264_CR31","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1016\/S0196-9781(01)00503-4","volume":"22","author":"H Tsubery","year":"2001","unstructured":"Tsubery, H., Ofek, I., Cohen, S. & Fridkin, M. N-terminal modifications of polymyxin B nonapeptide and their effect on antibacterial activity. Peptides 22, 1675\u20131681 (2001).","journal-title":"Peptides"},{"key":"4264_CR32","first-page":"e01415","volume":"56","author":"JD Lutgring","year":"2018","unstructured":"Lutgring, J. D. et al. FDA-CDC antimicrobial resistance isolate bank: a publicly available resource to support research, development, and regulatory requirements. J. Clin. Microbiol. 56, e01415-17 (2018).","journal-title":"J. Clin. Microbiol."},{"key":"4264_CR33","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1080\/00365510802150158","volume":"241","author":"P Devarajan","year":"2008","unstructured":"Devarajan, P. Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of kidney disease. Scand. J. Clin. Lab. Invest. Suppl. 241, 89\u201394 (2008).","journal-title":"Scand. J. Clin. Lab. Invest. Suppl."},{"key":"4264_CR34","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.3389\/fphar.2020.01146","volume":"11","author":"J Wang","year":"2020","unstructured":"Wang, J., Ishfaq, M., Fan, Q., Chen, C. & Li, J. 7-hydroxycoumarin attenuates colistin-induced kidney injury in mice through the decreased level of histone deacetylase 1 and the activation of Nrf2 signaling pathway. Front. Pharmacol. 11, 1146 (2020).","journal-title":"Front. Pharmacol."},{"key":"4264_CR35","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1053\/j.ajkd.2008.01.020","volume":"52","author":"D Bolignano","year":"2008","unstructured":"Bolignano, D. et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am. J. Kidney Dis. 52, 595\u2013605 (2008).","journal-title":"Am. J. Kidney Dis."},{"key":"4264_CR36","doi-asserted-by":"publisher","first-page":"D625","DOI":"10.1093\/nar\/gky1060","volume":"47","author":"K Blin","year":"2019","unstructured":"Blin, K. et al. The antiSMASH database version 2: a comprehensive resource on secondary metabolite biosynthetic gene clusters. Nucleic Acids Res. 47, D625\u2013D630 (2019).","journal-title":"Nucleic Acids Res."},{"key":"4264_CR37","doi-asserted-by":"publisher","first-page":"W81","DOI":"10.1093\/nar\/gkz310","volume":"47","author":"K Blin","year":"2019","unstructured":"Blin, K. et al. antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 47, W81\u2013W87 (2019).","journal-title":"Nucleic Acids Res."},{"key":"4264_CR38","unstructured":"Testing, E. C. O. A. S. Recommendations for MIC Determination of Colistin (Polymyxin E) as Recommended by the Joint CLSI-EUCAST Polymyxin Breakpoints Working Group (EUCAST, 2016)."},{"key":"4264_CR39","unstructured":"Wikler, M. A. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: approved standard. CLSI document M07-A7\u00a0(2006)."},{"key":"4264_CR40","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1128\/JB.00639-15","volume":"198","author":"J Bojkovic","year":"2015","unstructured":"Bojkovic, J. et al. Characterization of an Acinetobacter baumannii lptD deletion strain: permeability defects and response to inhibition of lipopolysaccharide and fatty acid biosynthesis. J. Bacteriol. 198, 731\u2013741 (2015).","journal-title":"J. Bacteriol."},{"key":"4264_CR41","first-page":"936","volume":"47","author":"J Carmichael","year":"1987","unstructured":"Carmichael, J., DeGraff, W. G., Gazdar, A. F., Minna, J. D. & Mitchell, J. B. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 47, 936\u2013942 (1987).","journal-title":"Cancer Res."}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-021-04264-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-021-04264-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-021-04264-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T21:04:17Z","timestamp":1643231057000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-021-04264-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,5]]},"references-count":41,"journal-issue":{"issue":"7894","published-print":{"date-parts":[[2022,1,27]]}},"alternative-id":["4264"],"URL":"https:\/\/doi.org\/10.1038\/s41586-021-04264-x","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.741410360.793591471","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.741410360.793591808","asserted-by":"object"}]},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,5]]},"assertion":[{"value":"20 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}