{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:44:46Z","timestamp":1791827086651,"version":"4.3.4"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"8","license":[{"start":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T00:00:00Z","timestamp":1597017600000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["115355"],"award-info":[{"award-number":["115355"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["139216"],"award-info":[{"award-number":["139216"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,2,25]]},"abstract":"<jats:p>\n                    The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is an essential lipid A biosynthetic enzyme that is conserved in the majority of gram-negative bacteria. It has emerged as an attractive novel antibiotic target due to the recent discovery of an LpxH-targeting sulfonyl piperazine compound (referred to as AZ1) by AstraZeneca. However, the molecular details of AZ1 inhibition have remained unresolved, stymieing further development of this class of antibiotics. Here we report the crystal structure of\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    LpxH in complex with AZ1. We show that AZ1 fits snugly into the\n                    <jats:italic>L<\/jats:italic>\n                    -shaped acyl chain-binding chamber of LpxH with its indoline ring situating adjacent to the active site, its sulfonyl group adopting a sharp kink, and its\n                    <jats:italic>N<\/jats:italic>\n                    -CF\n                    <jats:sub>3<\/jats:sub>\n                    \u2013phenyl substituted piperazine group reaching out to the far side of the LpxH acyl chain-binding chamber. Intriguingly, despite the observation of a single AZ1 conformation in the crystal structure, our solution NMR investigation has revealed the presence of a second ligand conformation invisible in the crystalline state. Together, these distinct ligand conformations delineate a cryptic inhibitor envelope that expands the observed footprint of AZ1 in the LpxH-bound crystal structure and enables the design of AZ1 analogs with enhanced potency in enzymatic assays. These designed compounds display striking improvement in antibiotic activity over AZ1 against wild-type\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    , and coadministration with outer membrane permeability enhancers profoundly sensitizes\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    to designed LpxH inhibitors. Remarkably, none of the sulfonyl piperazine compounds occupies the active site of LpxH, foretelling a straightforward path for rapid optimization of this class of antibiotics.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1912876117","type":"journal-article","created":{"date-parts":[[2020,2,10]],"date-time":"2020-02-10T20:25:59Z","timestamp":1581366359000},"page":"4109-4116","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":38,"title":["Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics"],"prefix":"10.1073","volume":"117","author":[{"given":"Jae","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Duke University Medical Center, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University, Durham, NC 27708"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Skyler","family":"Cochrane","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University, Durham, NC 27708"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline G.","family":"Webster","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University, Durham, NC 27708"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Fenton","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Duke University Medical Center, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinshi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Duke University Medical Center, Durham, NC 27710;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5253-0949","authenticated-orcid":false,"given":"Jiyong","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University, Durham, NC 27708"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7823-3416","authenticated-orcid":false,"given":"Pei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Duke University Medical Center, Durham, NC 27710;"},{"name":"Department of Chemistry, Duke University, Durham, NC 27708"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,2,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1086\/595011","article-title":"Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America","volume":"48","author":"Boucher H. W.","year":"2009","unstructured":"H. W. Boucher ., Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America. Clin. Infect. Dis. 48, 1\u201312 (2009).","journal-title":"Clin. Infect. Dis."},{"key":"e_1_3_4_2_2","unstructured":"World Health Organization Global priority list of antibiotic-resistant bacteria to guide research discovery and development of new antibiotics (2017). https:\/\/www.who.int\/medicines\/publications\/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf. Accessed 1 June 2019."},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1146\/annurev.biochem.71.110601.135414","article-title":"Lipopolysaccharide endotoxins","volume":"71","author":"Raetz C. R. H.","year":"2002","unstructured":"C. R. H. Raetz, C. Whitfield, Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635\u2013700 (2002).","journal-title":"Annu. Rev. 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Biotechnol."},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.2174\/092986712800167374","article-title":"UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) inhibitors: A new class of antibacterial agents","volume":"19","author":"Zhang J.","year":"2012","unstructured":"J. Zhang, L. Zhang, X. Li, W. Xu, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) inhibitors: A new class of antibacterial agents. Curr. Med. Chem. 19, 2038\u20132050 (2012).","journal-title":"Curr. Med. Chem."},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.chembiol.2010.11.011","article-title":"Species-specific and inhibitor-dependent conformations of LpxC: Implications for antibiotic design","volume":"18","author":"Lee C. J.","year":"2011","unstructured":"C. J. Lee ., Species-specific and inhibitor-dependent conformations of LpxC: Implications for antibiotic design. Chem. 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Science 274, 980\u2013982 (1996).","journal-title":"Science"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1021\/jm2014748","article-title":"Potent inhibitors of LpxC for the treatment of Gram-negative infections","volume":"55","author":"Brown M. F.","year":"2012","unstructured":"M. F. Brown ., Potent inhibitors of LpxC for the treatment of Gram-negative infections. J. Med. Chem. 55, 914\u2013923 (2012).","journal-title":"J. Med. Chem."},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1021\/jm2014875","article-title":"Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections","volume":"55","author":"Montgomery J. I.","year":"2012","unstructured":"J. I. Montgomery ., Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections. J. Med. Chem. 55, 1662\u20131670 (2012).","journal-title":"J. Med. Chem."},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.carres.2012.06.006","article-title":"Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue","volume":"359","author":"Oddo A.","year":"2012","unstructured":"A. Oddo, R. Holl, Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue. Carbohydr. Res. 359, 59\u201364 (2012).","journal-title":"Carbohydr. Res."},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1016\/j.bmcl.2012.01.140","article-title":"Structure based design of an in vivo active hydroxamic acid inhibitor of P. aeruginosa LpxC","volume":"22","author":"Warmus J. S.","year":"2012","unstructured":"J. S. Warmus ., Structure based design of an in vivo active hydroxamic acid inhibitor of P. aeruginosa LpxC. Bioorg. Med. Chem. Lett. 22, 2536\u20132543 (2012).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.bmc.2013.12.057","article-title":"Synthesis, biological evaluation and molecular docking studies of benzyloxyacetohydroxamic acids as LpxC inhibitors","volume":"22","author":"Szermerski M.","year":"2014","unstructured":"M. Szermerski ., Synthesis, biological evaluation and molecular docking studies of benzyloxyacetohydroxamic acids as LpxC inhibitors. Bioorg. Med. Chem. 22, 1016\u20131028 (2014).","journal-title":"Bioorg. Med. Chem."},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"6056","DOI":"10.1039\/c3ob41082j","article-title":"Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors","volume":"11","author":"L\u00f6ppenberg M.","year":"2013","unstructured":"M. L\u00f6ppenberg ., Synthesis and biological evaluation of flexible and conformationally constrained LpxC inhibitors. Org. Biomol. Chem. 11, 6056\u20136070 (2013).","journal-title":"Org. Biomol. Chem."},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1016\/j.bmcl.2013.02.055","article-title":"Exploring the UDP pocket of LpxC through amino acid analogs","volume":"23","author":"Hale M. R.","year":"2013","unstructured":"M. R. Hale ., Exploring the UDP pocket of LpxC through amino acid analogs. Bioorg. Med. Chem. Lett. 23, 2362\u20132367 (2013).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"6832","DOI":"10.1016\/j.bmcl.2012.09.058","article-title":"Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as Gram-negative antibacterial agents","volume":"22","author":"McAllister L. A.","year":"2012","unstructured":"L. A. McAllister ., Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as Gram-negative antibacterial agents. Bioorg. Med. Chem. Lett. 22, 6832\u20136838 (2012).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"e00312-12","DOI":"10.1128\/mBio.00312-12","article-title":"Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis","volume":"3","author":"Lin L.","year":"2012","unstructured":"L. Lin ., Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. mBio 3, e00312-12 (2012).","journal-title":"mBio"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"e00674-17","DOI":"10.1128\/mBio.00674-17","article-title":"Curative treatment of severe Gram-negative bacterial infections by a new class of antibiotics targeting LpxC","volume":"8","author":"Lemaitre N.","year":"2017","unstructured":"N. Lemaitre ., Curative treatment of severe Gram-negative bacterial infections by a new class of antibiotics targeting LpxC. mBio 8, e00674-17 (2017).","journal-title":"mBio"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"25947","DOI":"10.1074\/jbc.M204068200","article-title":"Accumulation of the lipid A precursor UDP-2,3-diacylglucosamine in an Escherichia coli mutant lacking the lpxH gene","volume":"277","author":"Babinski K. J.","year":"2002","unstructured":"K. J. Babinski, S. J. Kanjilal, C. R. Raetz, Accumulation of the lipid A precursor UDP-2,3-diacylglucosamine in an Escherichia coli mutant lacking the lpxH gene. J. Biol. Chem. 277, 25947\u201325956 (2002).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1128\/JB.02552-14","article-title":"Novel antibacterial targets and compounds revealed by a high-throughput cell wall reporter assay","volume":"197","author":"Nayar A. S.","year":"2015","unstructured":"A. S. Nayar ., Novel antibacterial targets and compounds revealed by a high-throughput cell wall reporter assay. J. Bacteriol. 197, 1726\u20131734 (2015).","journal-title":"J. Bacteriol."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"16154","DOI":"10.1038\/nmicrobiol.2016.154","article-title":"Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis","volume":"1","author":"Cho J.","year":"2016","unstructured":"J. Cho, C. J. Lee, J. Zhao, H. E. Young, P. Zhou, Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis. Nat. Microbiol. 1, 16154 (2016).","journal-title":"Nat. Microbiol."},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"26987","DOI":"10.1074\/jbc.M113.497636","article-title":"The UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis utilizes Mn2+ cluster for catalysis","volume":"288","author":"Young H. E.","year":"2013","unstructured":"H. E. Young, M. P. Donohue, T. I. Smirnova, A. I. Smirnov, P. Zhou, The UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis utilizes Mn2+ cluster for catalysis. J. Biol. Chem. 288, 26987\u201327001 (2013).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"6715","DOI":"10.1021\/bi1008744","article-title":"An alternative route for UDP-diacylglucosamine hydrolysis in bacterial lipid A biosynthesis","volume":"49","author":"Metzger L. E.","year":"2010","unstructured":"L. E. Metzger 4th, C. R. Raetz, An alternative route for UDP-diacylglucosamine hydrolysis in bacterial lipid A biosynthesis. Biochemistry 49, 6715\u20136726 (2010).","journal-title":"Biochemistry"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"e00090","DOI":"10.1128\/mBio.00090-16","article-title":"Discovery of the elusive UDP-Diacylglucosamine hydrolase in the lipid A biosynthetic pathway in Chlamydia trachomatis","volume":"7","author":"Young H. E.","year":"2016","unstructured":"H. E. Young ., Discovery of the elusive UDP-Diacylglucosamine hydrolase in the lipid A biosynthetic pathway in Chlamydia trachomatis. MBio 7, e00090 (2016).","journal-title":"MBio"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1021\/acsinfecdis.8b00364","article-title":"Structure-activity relationship of sulfonyl piperazine LpxH inhibitors analyzed by an LpxE-coupled malachite green assay","volume":"5","author":"Lee M.","year":"2019","unstructured":"M. Lee ., Structure-activity relationship of sulfonyl piperazine LpxH inhibitors analyzed by an LpxE-coupled malachite green assay. ACS Infect. Dis. 5, 641\u2013651 (2019).","journal-title":"ACS Infect. Dis."},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1111\/j.1365-2958.2007.06074.x","article-title":"Single amino acid substitutions in either YhjD or MsbA confer viability to 3-deoxy-d-manno-oct-2-ulosonic acid-depleted Escherichia coli","volume":"67","author":"Mamat U.","year":"2008","unstructured":"U. Mamat ., Single amino acid substitutions in either YhjD or MsbA confer viability to 3-deoxy-d-manno-oct-2-ulosonic acid-depleted Escherichia coli. Mol. Microbiol. 67, 633\u2013648 (2008).","journal-title":"Mol. Microbiol."},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"32822","DOI":"10.1038\/srep32822","article-title":"Crystal structures of the UDP-diacylglucosamine pyrophosphohydrase LpxH from Pseudomonas aeruginosa","volume":"6","author":"Okada C.","year":"2016","unstructured":"C. Okada ., Crystal structures of the UDP-diacylglucosamine pyrophosphohydrase LpxH from Pseudomonas aeruginosa. Sci. Rep. 6, 32822 (2016).","journal-title":"Sci. Rep."},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"9459","DOI":"10.1073\/pnas.96.17.9459","article-title":"Cation-pi interactions in structural biology","volume":"96","author":"Gallivan J. P.","year":"1999","unstructured":"J. P. Gallivan, D. A. Dougherty, Cation-pi interactions in structural biology. Proc. Natl. Acad. Sci. U.S.A. 96, 9459\u20139464 (1999).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"7969","DOI":"10.1074\/jbc.RA118.002503","article-title":"The substrate-binding cap of the UDP-diacylglucosamine pyrophosphatase LpxH is highly flexible, enabling facile substrate binding and product release","volume":"293","author":"Bohl T. E.","year":"2018","unstructured":"T. E. Bohl ., The substrate-binding cap of the UDP-diacylglucosamine pyrophosphatase LpxH is highly flexible, enabling facile substrate binding and product release. J. Biol. Chem. 293, 7969\u20137981 (2018).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"4405","DOI":"10.1021\/cr1002722","article-title":"Aliphatic diazirines as photoaffinity probes for proteins: Recent developments","volume":"111","author":"Das J.","year":"2011","unstructured":"J. Das, Aliphatic diazirines as photoaffinity probes for proteins: Recent developments. Chem. Rev. 111, 4405\u20134417 (2011).","journal-title":"Chem. Rev."},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"10638","DOI":"10.1038\/ncomms10638","article-title":"Drug design from the cryptic inhibitor envelope","volume":"7","author":"Lee C. J.","year":"2016","unstructured":"C. J. Lee ., Drug design from the cryptic inhibitor envelope. Nat. Commun. 7, 10638 (2016).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/275247a0","article-title":"Dynamic model of globular protein conformations based on NMR studies in solution","volume":"275","author":"Wagner G.","year":"1978","unstructured":"G. Wagner, K. W\u00fcthrich, Dynamic model of globular protein conformations based on NMR studies in solution. Nature 275, 247\u2013248 (1978).","journal-title":"Nature"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"3085","DOI":"10.1021\/jm0000057","article-title":"Structure-function studies of polymyxin B nonapeptide: Implications to sensitization of gram-negative bacteria","volume":"43","author":"Tsubery H.","year":"2000","unstructured":"H. Tsubery, I. Ofek, S. Cohen, M. Fridkin, Structure-function studies of polymyxin B nonapeptide: Implications to sensitization of gram-negative bacteria. J. Med. Chem. 43, 3085\u20133092 (2000).","journal-title":"J. Med. Chem."},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1126\/science.274.5292.1531","article-title":"Discovering high-affinity ligands for proteins: SAR by NMR","volume":"274","author":"Shuker S. B.","year":"1996","unstructured":"S. B. Shuker, P. J. Hajduk, R. P. Meadows, S. W. Fesik, Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 1531\u20131534 (1996).","journal-title":"Science"},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","first-page":"17028","DOI":"10.1038\/nmicrobiol.2017.28","article-title":"Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance","volume":"2","author":"Stokes J. M.","year":"2017","unstructured":"J. M. Stokes ., Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance. Nat. Microbiol. 2, 17028 (2017).","journal-title":"Nat. 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Nara ., Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors. Bioorg. Med. Chem. 24, 6149\u20136165 (2016).","journal-title":"Bioorg. Med. Chem."},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","first-page":"e6720","DOI":"10.1371\/journal.pone.0006720","article-title":"The role of relA and spoT in Yersinia pestis KIM5 pathogenicity","volume":"4","author":"Sun W.","year":"2009","unstructured":"W. Sun, K. L. Roland, C. G. Branger, X. Kuang, R. Curtiss 3rd, The role of relA and spoT in Yersinia pestis KIM5 pathogenicity. PLoS One 4, e6720 (2009).","journal-title":"PLoS One"},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","first-page":"6640","DOI":"10.1073\/pnas.120163297","article-title":"One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products","volume":"97","author":"Datsenko K. A.","year":"2000","unstructured":"K. A. Datsenko, B. L. Wanner, One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl. Acad. Sci. U.S.A. 97, 6640\u20136645 (2000).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_43_2","doi-asserted-by":"crossref","first-page":"9627","DOI":"10.1021\/bi901391g","article-title":"Replacement of lipopolysaccharide with free lipid A molecules in Escherichia coli mutants lacking all core sugars","volume":"48","author":"Reynolds C. M.","year":"2009","unstructured":"C. M. Reynolds, C. R. Raetz, Replacement of lipopolysaccharide with free lipid A molecules in Escherichia coli mutants lacking all core sugars. 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Biol."},{"key":"e_1_3_4_45_2","volume-title":"Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically","author":"Standards NCfCL","year":"1997","unstructured":"Standards NCfCL, Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically (Approved Standard, NCCLS document M7-A1, Wayne, PA, 1997)."},{"key":"e_1_3_4_46_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1023\/A:1011258906244","article-title":"A solubility-enhancement tag (SET) for NMR studies of poorly behaving proteins","volume":"20","author":"Zhou P.","year":"2001","unstructured":"P. Zhou, A. A. Lugovskoy, G. Wagner, A solubility-enhancement tag (SET) for NMR studies of poorly behaving proteins. J. Biomol. NMR 20, 11\u201314 (2001).","journal-title":"J. Biomol. 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Crystallogr."},{"key":"e_1_3_4_49_2","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1107\/S0907444909029436","article-title":"Electronic ligand builder and optimization workbench (eLBOW): A tool for ligand coordinate and restraint generation","volume":"65","author":"Moriarty N. W.","year":"2009","unstructured":"N. W. Moriarty, R. W. Grosse-Kunstleve, P. D. Adams, Electronic ligand builder and optimization workbench (eLBOW): A tool for ligand coordinate and restraint generation. Acta Crystallogr. D Biol. Crystallogr. 65, 1074\u20131080 (2009).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"e_1_3_4_50_2","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1107\/S0907444904019158","article-title":"Coot: Model-building tools for molecular graphics","volume":"60","author":"Emsley P.","year":"2004","unstructured":"P. Emsley, K. Cowtan, Coot: Model-building tools for molecular graphics. Acta Crystallogr. D Biol. 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