{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:25:39Z","timestamp":1756189539533,"version":"3.40.5"},"reference-count":95,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R03AI151205","R03AI171448","R21AI137641"],"award-info":[{"award-number":["R03AI151205","R03AI171448","R21AI137641"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The dipeptide D\u2010Ala\u2010D\u2010Ala is an essential component of peptidoglycan and the target of vancomycin. Most <jats:italic>Clostridioides difficile<\/jats:italic> strains possess the <jats:italic>vanG<\/jats:italic> operon responsible for the synthesis of D\u2010Ala\u2010D\u2010Ser, which can replace D\u2010Ala\u2010D\u2010Ala in peptidoglycan. The <jats:italic>C. difficile vanG<\/jats:italic> operon is regulated by a two\u2010component system, VanRS, but is not induced sufficiently by vancomycin to confer resistance to this antibiotic. Surprisingly, in the absence of the VanS histidine kinase (HK), the <jats:italic>vanG<\/jats:italic> operon is still induced by vancomycin and also by another antibiotic, ramoplanin, in a VanR\u2010dependent manner. This suggested the cross\u2010regulation of VanR by another HK or kinases that are activated in the presence of certain lipid II\u2010targeting antibiotics. We identified these HKs as CD35990 and CD22880. However, mutations in either or both HKs did not affect the regulation of the <jats:italic>vanG<\/jats:italic> operon in wild\u2010type cells suggesting that intact VanS prevents the cross\u2010activation of VanR by non\u2010cognate HKs. Overproduction of VanR in the absence of VanS, CD35990, and CD22880 led to high expression of the <jats:italic>vanG<\/jats:italic> operon indicating that VanR can potentially utilize at least one more phosphate donor for its activation. Candidate targets of CD35990\u2010 and CD22880\u2010mediated regulation in the presence of vancomycin or ramoplanin were identified by RNA\u2010Seq.<\/jats:p>","DOI":"10.1111\/mmi.15273","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T10:38:20Z","timestamp":1714559900000},"page":"1182-1199","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Histidine kinase\u2010mediated cross\u2010regulation of the vancomycin\u2010resistance operon in <i>Clostridioides difficile<\/i>"],"prefix":"10.1111","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0171-3128","authenticated-orcid":false,"given":"Boris R.","family":"Belitsky","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Microbiology Tufts University School of Medicine  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,5]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.184.23.6457-6464.2002"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0064875"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1139\/w2012-002"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12299"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.000917"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2010-11-10-r106"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1099\/13500872-145-8-1849"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.179.1.97-106.1997"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.10.2291"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1997.4401812.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1999.01308.x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2008.00104.x"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.14980"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.180.23.6298-6305.1998"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780471729259.mc09a02s20"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.14371"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01492-12"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","unstructured":"Buddle J.E. Wright R.C.T. Turner C.E. Chaudhuri R.R. Brockhurst M.A.&Fagan R.P.(2023)Multiple evolutionary pathways lead to vancomycin resistance inClostridioides difficile. bioRxiv: 2023.2009.2015.557922.","DOI":"10.1101\/2023.09.15.557922"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2002.03050.x"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.45817-0"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.02525-09"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00489-22"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa912"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-46718-4_20"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01348-08"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.10.3892-3904.2004"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005170"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1998.00663.x"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M005872200"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010841"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.00106-22"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.263889"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000379"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-102215-095331"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms9102026"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.187.23.8205-8210.2005"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.179.18.5903-5913.1997"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-5521(00)00116-2"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr1321"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00351-18"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.641756"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-12-226"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-78885-2_14"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.45790-0"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2005.04953.x"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2011.07829.x"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciab549"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2007.00091.x"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00995-15"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03599.x"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.41.042007.170548"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa051639"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005758"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S215070"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy149"},{"volume-title":"Experiments in molecular genetics","year":"1972","author":"Miller J.H.","key":"e_1_2_10_58_1"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.00121-22"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)60372-2"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0056051"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2009.06987.x"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01367-15"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05315.x"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-021-04311-5"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjsurg.2016.10.035"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.03397-22"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.00164-23"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.065060-0"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2018.00096"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-160"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.142.7.624"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.anaerobe.2019.102072"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.69.4.585-607.2005"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijmm.2009.10.005"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1830"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkz513"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3313"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.20.11951"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-72799-8_9"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.69.1.183"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3819"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00166-13"},{"key":"e_1_2_10_84_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbs017"},{"key":"e_1_2_10_85_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41396-021-01042-5"},{"key":"e_1_2_10_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(91)90546-N"},{"key":"e_1_2_10_87_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00882-09"},{"key":"e_1_2_10_88_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0210627"},{"key":"e_1_2_10_89_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2007.00094.x"},{"key":"e_1_2_10_90_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.03777-22"},{"key":"e_1_2_10_91_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003084"},{"key":"e_1_2_10_92_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01710-09"},{"key":"e_1_2_10_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(85)90120-9"},{"key":"e_1_2_10_94_1","doi-asserted-by":"publisher","DOI":"10.1111\/gtc.12251"},{"key":"e_1_2_10_95_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a026989"},{"key":"e_1_2_10_96_1","doi-asserted-by":"publisher","DOI":"10.2144\/01304pf02"}],"container-title":["Molecular Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/mmi.15273","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T03:52:37Z","timestamp":1718250757000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/mmi.15273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5]]},"references-count":95,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,6]]}},"alternative-id":["10.1111\/mmi.15273"],"URL":"https:\/\/doi.org\/10.1111\/mmi.15273","archive":["Portico"],"relation":{},"ISSN":["0950-382X","1365-2958"],"issn-type":[{"type":"print","value":"0950-382X"},{"type":"electronic","value":"1365-2958"}],"subject":[],"published":{"date-parts":[[2024,5]]},"assertion":[{"value":"2024-02-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}