{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:12:36Z","timestamp":1790871156606,"version":"4.1.0"},"reference-count":82,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T00:00:00Z","timestamp":1527811200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100000082","name":"Cystic Fibrosis Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000082","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["2015-05916"],"award-info":[{"award-number":["2015-05916"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003151","name":"Fonds de Recherche du Qu\u00e9bec-Nature et Technologies","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003151","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003151","name":"Fonds de Recherche du Qu\u00e9bec-Nature et Technologies","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003151","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Methicillin-resistant\n            <jats:named-content content-type=\"genus-species\">Staphylococcus aureus<\/jats:named-content>\n            (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-\n            <jats:named-content content-type=\"genus-species\">Staphylococcus<\/jats:named-content>\n            antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            small-colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of\n            <jats:italic>in vitro<\/jats:italic>\n            -generated TO-resistant\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences, and the structural consequences of the mutations were evaluated in structural models. Overexpression of the\n            <jats:italic>atpE<\/jats:italic>\n            gene in\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            SCVs or introducing the mutation found in the\n            <jats:italic>atpE<\/jats:italic>\n            gene of one of the high-level TO-resistant\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            mutants into the\n            <jats:named-content content-type=\"genus-species\">Bacillus subtilis atpE<\/jats:named-content>\n            gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria versus that of bacterial ATP synthase) is estimated to be &gt;10\n            <jats:sup>5<\/jats:sup>\n            -fold for FC04-100.\n          <\/jats:p>","DOI":"10.1128\/aac.02197-17","type":"journal-article","created":{"date-parts":[[2018,3,30]],"date-time":"2018-03-30T13:31:17Z","timestamp":1522416677000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":72,"title":["Tomatidine Is a Lead Antibiotic Molecule That Targets Staphylococcus aureus ATP Synthase Subunit C"],"prefix":"10.1128","volume":"62","author":[{"given":"Maxime","family":"Lamontagne Boulet","sequence":"first","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Isabelle","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Guay","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Brouillette","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Langlois","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-\u00c9tienne","family":"Jacques","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Rodrigue","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryszard","family":"Brzezinski","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale B.","family":"Beauregard","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Bouarab","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumaraswamy","family":"Boyapelly","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pharmacologie, Facult\u00e9 de M\u00e9decine et des Sciences de la Sant\u00e9, Universit\u00e9 de Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Luc","family":"Boudreault","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pharmacologie, Facult\u00e9 de M\u00e9decine et des Sciences de la Sant\u00e9, Universit\u00e9 de Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9ric","family":"Marsault","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pharmacologie, Facult\u00e9 de M\u00e9decine et des Sciences de la Sant\u00e9, Universit\u00e9 de Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5031-345X","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Malouin","sequence":"additional","affiliation":[{"name":"Centre d'\u00c9tude et de Valorisation de la Diversit\u00e9 Microbienne, D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","unstructured":"Review on Antimicrobial Resistance. 2014. Antimicrobial resistance: tackling a crisis for the health and wealth of nations. The Review on Antimicrobial Resistance London United Kingdom. https:\/\/amr-review.org\/sites\/default\/files\/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/595011"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01250.x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1114021"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2012.00018"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2013.00138"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00030-10"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.4103\/2229-516X.112228"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01393-08"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106753"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr510"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01468-10"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40360-018-0197-2"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.4161\/viru.21523"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00081-09"},{"key":"e_1_3_3_17_2","volume-title":"Antibiotic resistance threats in the United States, 2013","author":"Centers for Disease Control and Prevention","year":"2013","unstructured":"Centers for Disease Control and Prevention. 2013. Antibiotic resistance threats in the United States, 2013. Centers for Disease Control and Prevention, Atlanta, GA. https:\/\/www.cdc.gov\/drugresistance\/threat-report-2013\/."},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tvjl.2006.11.008"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(11)70126-8"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics4040521"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/lam.12735"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.14.3.584-640.2001"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00073-09"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.4315\/0362-028X.JFP-13-150"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-food-030713-092332"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.2174\/092986711797636036"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1089\/fpd.2008.0110"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit270"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1384"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00069-15"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.188.1.64-76.2006"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-10-33"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.009720-0"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2009.10.003"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2008.11.004"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00078-11"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201000115"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2013.11.019"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00273-12"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.339.6116.130"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06154-11"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/elps.1150181505"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1094\/PHYTO.1998.88.2.137"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0031-9422(00)98476-0"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00829-17"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182012000522"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1093\/gbe\/evp036"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00289-06"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(01)02051-5"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biophys.37.032807.130018"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.78.081307.104803"},{"key":"e_1_3_3_52_2","first-page":"623","article-title":"Screening of essential genes in Staphylococcus aureus N315 using comparative genomics and allelic replacement mutagenesis","volume":"16","author":"Ko KS","year":"2006","unstructured":"Ko KS, Lee JY, Song JH, Baek JY, Oh WS, Chun JS, Yoon HS. 2006. Screening of essential genes in Staphylococcus aureus N315 using comparative genomics and allelic replacement mutagenesis. J Microbiol Biotechnol 16:623\u2013632.","journal-title":"J Microbiol Biotechnol"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-1605(00)00305-6"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.176.22.6802-6811.1994"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201000796"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00774-06"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2014.00099"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.mi.47.100193.002301"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1557"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2009.12.011"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2474"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkv054"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/46224"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21376"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1500106"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00244-06"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00016-08"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.1996.tb07959.x"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.181.22.6996-7004.1999"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2002.03003.x"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.183.2.580-586.2001"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.4.1183-1194.2006"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-9-95"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086705"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.femsim.2003.12.007"},{"key":"e_1_3_3_76_2","volume-title":"CLSI document M100-S22","author":"Clinical and Laboratory Standards Institute","year":"2013","unstructured":"Clinical and Laboratory Standards Institute. 2013. Performance standards for antimicrobial susceptibility testing; twenty-second informational supplement. CLSI document M100-S22. Clinical and Laboratory Standards Institute, Wayne, PA."},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011840"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp347"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1268"},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.70.10.6076-6085.2004"},{"key":"e_1_3_3_81_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2672.2006.03127.x"},{"key":"e_1_3_3_82_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2008.06469.x"},{"key":"e_1_3_3_83_2","volume-title":"Molecular biological methods for Bacillus","author":"Harwood CR","year":"1990","unstructured":"Harwood CR, Cutting SM. 1990. Molecular biological methods for Bacillus. John Wiley & Sons, Chichester, United Kingdom."}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02197-17","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02197-17","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T21:18:10Z","timestamp":1645478290000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02197-17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6]]},"references-count":82,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018,6]]}},"alternative-id":["10.1128\/AAC.02197-17"],"URL":"https:\/\/doi.org\/10.1128\/aac.02197-17","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6]]},"assertion":[{"value":"2017-10-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-03-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02197-17"}}