{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:07:09Z","timestamp":1790809629698,"version":"4.1.0"},"reference-count":59,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2013,9,13]],"date-time":"2013-09-13T00:00:00Z","timestamp":1379030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"},{"start":{"date-parts":[[2013,10,1]],"date-time":"2013-10-01T00:00:00Z","timestamp":1380585600000},"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":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2013,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by\n            <jats:italic>TbrPDEB1<\/jats:italic>\n            and\n            <jats:italic>TbrPDEB2<\/jats:italic>\n            . These genes were genetically confirmed as essential, and a high-affinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced. Selection of mutagenized trypanosomes resulted in resistance to CpdA as well as cross-resistance to membrane-permeable cAMP analogues but not to currently used trypanocidal drugs. Resistance was not due to changes in cAMP levels or in\n            <jats:italic>PDEB<\/jats:italic>\n            genes. A second approach, a genome-wide RNA interference (RNAi) library screen, returned four genes giving resistance to CpdA upon knockdown. Validation by independent RNAi strategies confirmed resistance to CpdA and suggested a role for the identified\n            <jats:underline>cA<\/jats:underline>\n            MP\n            <jats:underline>R<\/jats:underline>\n            esponse\n            <jats:underline>P<\/jats:underline>\n            roteins (CARPs) in cAMP action. CARP1 is unique to kinetoplastid parasites and has predicted cyclic nucleotide binding-like domains, and RNAi repression resulted in &gt;100-fold resistance. CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome or with flagellar function, with an orthologue of CARP4 implicated in human disease. CARP3 is a hypothetical protein, unique to\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trypanosoma<\/jats:named-content>\n            . CARP1 to CARP4 likely represent components of a novel cAMP signaling pathway in the parasite. As cAMP metabolism is validated as a drug target in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trypanosoma brucei<\/jats:named-content>\n            , cAMP effectors highly divergent from the mammalian host, such as\n            <jats:italic>CARP1<\/jats:italic>\n            , lend themselves to further pharmacological development.\n          <\/jats:p>","DOI":"10.1128\/aac.00508-13","type":"journal-article","created":{"date-parts":[[2013,7,23]],"date-time":"2013-07-23T02:15:44Z","timestamp":1374545744000},"page":"4882-4893","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":66,"title":["Cyclic AMP Effectors in African Trypanosomes Revealed by Genome-Scale RNA Interference Library Screening for Resistance to the Phosphodiesterase Inhibitor CpdA"],"prefix":"10.1128","volume":"57","author":[{"given":"Matthew K.","family":"Gould","sequence":"first","affiliation":[{"name":"Institute of Infection, Immunity &amp; Inflammation, College of Medical, Veterinary &amp; Life Sciences, University of Glasgow, Glasgow, United Kingdom"},{"name":"Centre for Immunity, Infection &amp; Evolution, Institute of Immunology &amp; Infection Research, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Bachmaier","sequence":"additional","affiliation":[{"name":"Biocenter, Section Genetics, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juma A. M.","family":"Ali","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity &amp; Inflammation, College of Medical, Veterinary &amp; Life Sciences, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Alsford","sequence":"additional","affiliation":[{"name":"Faculty of Infectious &amp; Tropical Diseases, London School of Hygiene &amp; Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel N. A.","family":"Tagoe","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity &amp; Inflammation, College of Medical, Veterinary &amp; Life Sciences, University of Glasgow, Glasgow, United Kingdom"},{"name":"Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane C.","family":"Munday","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity &amp; Inflammation, College of Medical, Veterinary &amp; Life Sciences, University of Glasgow, Glasgow, United Kingdom"},{"name":"Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achim C.","family":"Schnaufer","sequence":"additional","affiliation":[{"name":"Centre for Immunity, Infection &amp; Evolution, Institute of Immunology &amp; Infection Research, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Horn","sequence":"additional","affiliation":[{"name":"Faculty of Infectious &amp; Tropical Diseases, London School of Hygiene &amp; Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Boshart","sequence":"additional","affiliation":[{"name":"Biocenter, Section Genetics, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry P.","family":"de Koning","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity &amp; Inflammation, College of Medical, Veterinary &amp; Life Sciences, University of Glasgow, Glasgow, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1079\/9780851994758.0219"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1079\/9780851994758.0369"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2009.08.001"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-072X-9-57"},{"key":"e_1_3_3_6_2","first-page":"69","article-title":"Human African trypanosomiasis (sleeping sickness): epidemiological update","volume":"81","author":"World Health Organization","year":"2006","unstructured":"World Health Organization. 2006. Human African trypanosomiasis (sleeping sickness): epidemiological update. Wkly. Epidemiol. Rec. 81:69\u201380.","journal-title":"Wkly. Epidemiol. Rec."},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60829-1"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.11.44"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1086\/649917"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(99)00206-6"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.031351"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202885109"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2012.12.005"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000720"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1222753"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.2174\/1566524043360113"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2005.09.018"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2010.00262.x"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-6818com"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir857"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm201148s"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2012.08013.x"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm301059b"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.2307\/3282883"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(99)00002-X"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(02)00238-4"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2007.02.008"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2005.09.002"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2007.03.012"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0001-706X(97)00079-X"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2008.07.036"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-6851(93)90231-L"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2010.11.010"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.115089.110"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10771"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-6851(96)02598-4"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1550-7408.1999.tb04592.x"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2010.03.007"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M408111200"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1112642"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp851"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq237"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04541"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.200700607"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1143609"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00450-7"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.7.1689"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.200800477"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00248-10"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2003.10.007"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.062716599"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/9783527670383.ch18"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.110.21.2661"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0608971103"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.0014-2956.2001.02564.x"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03352"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2010.05.006"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.12.3.1218-1225.1992"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/cm.20129"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds356"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00508-13","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00508-13","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:33:53Z","timestamp":1645482833000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00508-13"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,10]]},"references-count":59,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2013,10]]}},"alternative-id":["10.1128\/AAC.00508-13"],"URL":"https:\/\/doi.org\/10.1128\/aac.00508-13","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,10]]},"assertion":[{"value":"2013-03-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-07-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-09-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}