{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:32:35Z","timestamp":1790505155023,"version":"4.1.0"},"reference-count":66,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2018,10,31]],"date-time":"2018-10-31T00:00:00Z","timestamp":1540944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,10,31]],"date-time":"2018-10-31T00:00:00Z","timestamp":1540944000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSphere"],"published-print":{"date-parts":[[2018,10,31]]},"abstract":"<jats:p>\n                    Emergence of antibiotic resistance has prompted efforts to identify and optimize novel inhibitors of antibacterial targets such as LpxC. This enzyme catalyzes the first committed step of lipid A synthesis, which is necessary to generate lipopolysaccharide and ultimately the Gram-negative protective outer membrane. Investigation of this pathway and its interrelationship with inner membrane (phospholipid) biosynthesis or other pathways is therefore highly important to the fundamental understanding of Gram-negative bacteria and by extension to antibiotic discovery. Here we exploited the availability of a novel LpxC inhibitor to engender the generation of\n                    <jats:named-content content-type=\"genus-species\">K. pneumoniae<\/jats:named-content>\n                    resistant mutants whose growth depends on chemical inhibition of LpxC. Inhibitor dependency resulted from the interaction of different resistance mutations and was based on loss of normal cellular mechanisms required to establish membrane homeostasis. This study provides new insights into the importance of this process in\n                    <jats:named-content content-type=\"genus-species\">K. pneumoniae<\/jats:named-content>\n                    and how it may be linked to novel biosynthetic pathway inhibitors.\n                  <\/jats:p>","DOI":"10.1128\/msphere.00508-18","type":"journal-article","created":{"date-parts":[[2018,10,30]],"date-time":"2018-10-30T07:39:32Z","timestamp":1540885172000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["Interplay of Klebsiella pneumoniae\n                    <i>fabZ<\/i>\n                    and\n                    <i>lpxC<\/i>\n                    Mutations Leads to LpxC Inhibitor-Dependent Growth Resulting from Loss of Membrane Homeostasis"],"prefix":"10.1128","volume":"3","author":[{"given":"Mina","family":"Mostafavi","sequence":"first","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisha","family":"Wang","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Xie","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth T.","family":"Takeoka","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daryl L.","family":"Richie","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fergal","family":"Casey","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Ruzin","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William S.","family":"Sawyer","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Rath","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Rong","family":"Wei","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9858-9818","authenticated-orcid":false,"given":"Charles R.","family":"Dean","sequence":"additional","affiliation":[{"name":"Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ja.2017.30"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12992-016-0147-y"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30753-3"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R800060-JLR200"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.71.110601.135414"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkw121"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00834-10"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-14609-0"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1611594113"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2013.09.007"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.56.3.632-639.1988"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-134-4-1009"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5289.980"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00377"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01551-14"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00407-16"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00312-12"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/ml500210x"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2013.12.057"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2013.02.055"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm2014748"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm2014875"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2012.09.058"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2010.12.111"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkw210"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.12.017"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm4007774"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm020183v"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb948"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi047820z"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709412104"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01600-09"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a025304"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2017.1360282"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05417-11"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.6.1793-1799.2002"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.447607"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1209742109"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00379-18"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)30075-2"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.3.1017-1022.2005"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004627"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1521168113"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0121216"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00270-08"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604744103"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1182749"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00639-15"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400067"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/36.6.585"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/36.6.598"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1997.4401812.x"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.6.1409"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01115-07"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02831-15"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi800240r"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi901025v"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005585"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0160918"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00199-17"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2005.04994.x"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.06.083"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01043-10"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.02134-12"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1999.01221.x"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.120163297"}],"container-title":["mSphere"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mSphere.00508-18","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mSphere.00508-18","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T23:17:17Z","timestamp":1646695037000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mSphere.00508-18"}},"subtitle":[],"editor":[{"given":"Paul","family":"Dunman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2018,10,31]]},"references-count":66,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,10,31]]}},"alternative-id":["10.1128\/mSphere.00508-18"],"URL":"https:\/\/doi.org\/10.1128\/msphere.00508-18","relation":{},"ISSN":["2379-5042"],"issn-type":[{"value":"2379-5042","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,31]]},"assertion":[{"value":"2018-09-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00508-18"}}