{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:47:13Z","timestamp":1790790433047,"version":"4.1.0"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"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":[[2014,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Heat shock protein 90 (Hsp90) is an essential chaperone involved in the fungal stress response that can be harnessed as a novel antifungal target for the treatment of invasive aspergillosis. We previously showed that genetic repression of Hsp90 reduced\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Aspergillus fumigatus<\/jats:named-content>\n            virulence and potentiated the effect of the echinocandin caspofungin. In this study, we sought to identify sites of posttranslational modifications (phosphorylation or acetylation) that are important for Hsp90 function in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. fumigatus<\/jats:named-content>\n            . Phosphopeptide enrichment and tandem mass spectrometry revealed phosphorylation of three residues in Hsp90 (S49, S288, and T681), but their mutation did not compromise Hsp90 function. Acetylation of lysine residues of Hsp90 was recovered after treatment with deacetylase inhibitors, and acetylation-mimetic mutations (K27A and K271A) resulted in reduced virulence in a murine model of invasive aspergillosis, supporting their role in Hsp90 function. A single deletion of lysine K27 or an acetylation-mimetic mutation (K27A) resulted in increased susceptibility to voriconazole and caspofungin. This effect was attenuated following a deacetylation-mimetic mutation (K27R), suggesting that this site is crucial and should be deacetylated for proper Hsp90 function in antifungal resistance pathways. In contrast to previous reports in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida albicans<\/jats:named-content>\n            , the lysine deacetylase inhibitor trichostatin A (TSA) was active alone against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. fumigatus<\/jats:named-content>\n            and potentiated the effect of caspofungin against both the wild type and an echinocandin-resistant strain. Our results indicate that the Hsp90 K27 residue is required for azole and echinocandin resistance in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. fumigatus<\/jats:named-content>\n            and that deacetylase inhibition may represent an adjunctive anti-\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Aspergillus<\/jats:named-content>\n            strategy.\n          <\/jats:p>","DOI":"10.1128\/aac.02286-13","type":"journal-article","created":{"date-parts":[[2014,1,7]],"date-time":"2014-01-07T03:18:30Z","timestamp":1389064710000},"page":"1889-1896","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":73,"title":["Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus"],"prefix":"10.1128","volume":"58","author":[{"given":"Fr\u00e9d\u00e9ric","family":"Lamoth","sequence":"first","affiliation":[{"name":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA"},{"name":"Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland"},{"name":"Institute of Microbiology, Lausanne University Hospital, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen R.","family":"Juvvadi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik J.","family":"Soderblom","sequence":"additional","affiliation":[{"name":"Duke Proteomics Core Facility, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Arthur","family":"Moseley","sequence":"additional","affiliation":[{"name":"Duke Proteomics Core Facility, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohannes G.","family":"Asfaw","sequence":"additional","affiliation":[{"name":"Division of Laboratory Animal Resources, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Steinbach","sequence":"additional","affiliation":[{"name":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA"},{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2012.08.003"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/525258"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1507.090043"},{"key":"e_1_3_3_5_2","volume-title":"abstr LB2812. Absourcestr.","author":"Marr K","year":"2012","unstructured":"MarrKSchlammHRottinghausSTJagannathaSBowEJWingardJRPappasPHebrechtRWalshTJMaertensJ. 2012. A randomised, double-bind study of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis, abstr LB2812. Absourcestr. 22nd Eur. Congr. Clin. Microbiol. Infect. Dis., London, United Kingdom, 31 March to 3 April 2012."},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1835"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813394106"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00032-12"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01857-12"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1716"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1118370"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000532"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit530"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2011.07.018"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.272"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.12.031"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.12.008"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C500186200"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.04.021"},{"key":"e_1_3_3_20_2","first-page":"5126","article-title":"Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells","volume":"63","author":"Nimmanapalli R","year":"2003","unstructured":"NimmanapalliRFuinoLBaliPGasparettoMGlozakMTaoJMoscinskiLSmithCWuJJoveRAtadjaPBhallaK. 2003. Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res. 63:5126\u20135135.","journal-title":"Cancer Res."},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/94.7.504"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.08.035"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.01.020"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/157.2.591"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1240"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212574200"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.405"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.10.6411-6418.2001"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00336-08"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2011.07886.x"},{"key":"e_1_3_3_31_2","first-page":"86","article-title":"Isolation and partial characterization of Hsp90 from Candida albicans","volume":"33","author":"Burt ET","year":"2003","unstructured":"BurtETDalyRHogansonDTsirulnikovYEssmannMLarsenB. 2003. Isolation and partial characterization of Hsp90 from Candida albicans. Ann. Clin. Lab. Sci. 33:86\u201393.","journal-title":"Ann. Clin. Lab. Sci."},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1080\/13693780410001712034"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00917-07"},{"key":"e_1_3_3_34_2","volume-title":"Reference method for broth dilution antifungal susceptibility testing of filamentous fungi","author":"Clinical and Laboratory Standards Institute","year":"2008","unstructured":"Clinical and Laboratory Standards Institute. 2008. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi, 2nd ed. CLSI document M38-A2. Clinical and Laboratory Standards Institute, Wayne, PA.","edition":"2"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1183147"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00618-09"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.11.3532-3539.2002"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201000489"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103921200"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.4.10.1736-1745.2005"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg473"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E09-08-0750"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.104.000638"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.116202"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.576"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02286-13","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02286-13","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:44:03Z","timestamp":1645483443000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02286-13"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4]]},"references-count":44,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2014,4]]}},"alternative-id":["10.1128\/AAC.02286-13"],"URL":"https:\/\/doi.org\/10.1128\/aac.02286-13","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4]]},"assertion":[{"value":"2013-10-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-01-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-03-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}