{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:03:46Z","timestamp":1772118226980,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,11,5]],"date-time":"2019-11-05T00:00:00Z","timestamp":1572912000000},"content-version":"am","delay-in-days":313,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2018,12,27]],"date-time":"2018-12-27T00:00:00Z","timestamp":1545868800000},"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":["1R21NS067579-01"],"award-info":[{"award-number":["1R21NS067579-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U54AI057141"],"award-info":[{"award-number":["U54AI057141"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000152","name":"Division of Molecular and Cellular Biosciences","doi-asserted-by":"publisher","award":["NSF Graduate Research Fellowship"],"award-info":[{"award-number":["NSF Graduate Research Fellowship"]}],"id":[{"id":"10.13039\/100000152","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["PA00P3- 124140"],"award-info":[{"award-number":["PA00P3- 124140"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["PBBSA-120489"],"award-info":[{"award-number":["PBBSA-120489"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["PA00P3-126243"],"award-info":[{"award-number":["PA00P3-126243"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008273","name":"Novartis Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008273","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The bacterial second messenger cyclic diguanosine monophosphate (c\u2010di\u2010GMP) is a key regulator of cellular motility, the cell cycle, and biofilm formation with its resultant antibiotic tolerance, which can make chronic infections difficult to treat. Therefore, diguanylate cyclases, which regulate the spatiotemporal production of c\u2010di\u2010GMP, might be attractive drug targets for control of biofilm formation that is part of chronic infections. We present a FRET\u2010based biochemical high\u2010throughput screening approach coupled with detailed structure\u2013activity studies to identify synthetic small\u2010molecule modulators of the diguanylate cyclase DgcA from\n                    <jats:italic>Caulobacter crescentus<\/jats:italic>\n                    . We identified a set of seven small molecules that regulate DgcA enzymatic activity in the low\u2010micromolar range. Subsequent structure\u2013activity studies on selected scaffolds revealed a remarkable diversity of modulatory behavior, including slight chemical substitutions that reverse the effects from allosteric enzyme inhibition to activation. The compounds identified represent new chemotypes and are potentially developable into chemical genetic tools for the dissection of c\u2010di\u2010GMP signaling networks and alteration of c\u2010di\u2010GMP\u2010associated phenotypes. In sum, our studies underline the importance of detailed mechanism\u2010of\u2010action studies for inhibitors of c\u2010di\u2010GMP signaling and demonstrate the complex interplay between synthetic small molecules and the regulatory mechanisms that control the activity of diguanylate cyclases.\n                  <\/jats:p>","DOI":"10.1002\/cbic.201800593","type":"journal-article","created":{"date-parts":[[2018,11,5]],"date-time":"2018-11-05T10:05:34Z","timestamp":1541412334000},"page":"394-407","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Identification of Small\u2010Molecule Modulators of Diguanylate Cyclase by FRET\u2010Based High\u2010Throughput Screening"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7724-4562","authenticated-orcid":false,"given":"Matthias","family":"Christen","sequence":"first","affiliation":[{"name":"Eidgen\u00f6ssische Technische Hochschule Z\u00fcrich Department of Biology  Auguste-Piccard-Hof 1 8093 Z\u00fcrich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cassandra","family":"Kamischke","sequence":"additional","affiliation":[{"name":"University of Washington Department of Microbiology  1959 NE Pacific St. Box 357710 Seattle WA 98195 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hemantha D.","family":"Kulasekara","sequence":"additional","affiliation":[{"name":"University of Washington Department of Microbiology  1959 NE Pacific St. Box 357710 Seattle WA 98195 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen C.","family":"Olivas","sequence":"additional","affiliation":[{"name":"Seattle Genetics, Inc.  21823 30th Drive SE Bothell WA 98021 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bridget R.","family":"Kulasekara","sequence":"additional","affiliation":[{"name":"University of Washington Department of Genome Sciences  1959 NE Pacific St., Box 357710 Seattle WA 98195 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beat","family":"Christen","sequence":"additional","affiliation":[{"name":"Eidgen\u00f6ssische Technische Hochschule Z\u00fcrich Department of Biology  Otto-Stern-Weg-3 8093 Z\u00fcrich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toni","family":"Kline","sequence":"additional","affiliation":[{"name":"Sutro Biopharma  310 Utah Avenue, Suite 150 San Francisco CA 94080 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel I.","family":"Miller","sequence":"additional","affiliation":[{"name":"University of Washington Department of Microbiology  1959 NE Pacific St. Box 357710 Seattle WA 98195 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,12,27]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03912"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2011.01619.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.MB-0003-2014"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3546"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12777"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.2001.tb10880.x"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03401.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0406134101"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)84115-7"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1188658"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.01402"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaa1796"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.289504"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6392"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12066"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja311960g"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2015.1062970"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.07.068"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/15257770802554150"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612820666140905124701"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.pcp.a029351"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb400485k"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01396-12"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/08927014.2013.832224"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05440.x"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00307-12"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1056-8719(00)00107-6"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.072845607"}],"container-title":["ChemBioChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcbic.201800593","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.201800593","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbic.201800593","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/am-pdf\/10.1002\/cbic.201800593","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.201800593","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T20:56:18Z","timestamp":1760302578000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cbic.201800593"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,27]]},"references-count":28,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2019,2]]}},"alternative-id":["10.1002\/cbic.201800593"],"URL":"https:\/\/doi.org\/10.1002\/cbic.201800593","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/402909","asserted-by":"object"}]},"ISSN":["1439-4227","1439-7633"],"issn-type":[{"value":"1439-4227","type":"print"},{"value":"1439-7633","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,27]]},"assertion":[{"value":"2018-10-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}