{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:18:40Z","timestamp":1789633120846,"version":"build-2803163510"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2017,7,1]],"date-time":"2017-07-01T00:00:00Z","timestamp":1498867200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["GM067871"],"award-info":[{"award-number":["GM067871"]}],"id":[{"id":"10.13039\/100000002","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":[[2017,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14\u03b1-demethylase (CYP51B) from the filamentous fungus<jats:named-content content-type=\"genus-species\">Aspergillus fumigatus<\/jats:named-content>. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 \u00b1 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598\/<jats:named-content content-type=\"genus-species\">A. fumigatus<\/jats:named-content>CYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis of<jats:named-content content-type=\"genus-species\">A. fumigatus<\/jats:named-content>CYP51\/voriconazole and<jats:named-content content-type=\"genus-species\">Candida albicans<\/jats:named-content>CYP51\/VT-1161 complexes supports the role of H bonding in fungal CYP51\/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using two<jats:named-content content-type=\"genus-species\">A. fumigatus<\/jats:named-content>strains (strains 32820 and 1022) displayed a direct correlation between the effects of the drugs on CYP51B activity and fungal growth inhibition, indicating the noteworthy anti-<jats:named-content content-type=\"genus-species\">A. fumigatus<\/jats:named-content>potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent.<\/jats:p>","DOI":"10.1128\/aac.00570-17","type":"journal-article","created":{"date-parts":[[2017,5,2]],"date-time":"2017-05-02T00:20:41Z","timestamp":1493684441000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":66,"title":["Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14\u03b1-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity"],"prefix":"10.1128","volume":"61","author":[{"given":"Tatiana Y.","family":"Hargrove","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward P.","family":"Garvey","sequence":"additional","affiliation":[{"name":"Viamet Pharmaceuticals, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Hoekstra","sequence":"additional","affiliation":[{"name":"Viamet Pharmaceuticals, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Yates","sequence":"additional","affiliation":[{"name":"Viamet Pharmaceuticals, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zdzislaw","family":"Wawrzak","sequence":"additional","affiliation":[{"name":"Synchrotron Research Center, Life Science Collaborative Access Team, Northwestern University, Argonne, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girish","family":"Rachakonda","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Villalta","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina I.","family":"Lepesheva","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"},{"name":"Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004404"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa6097"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.2147\/TCRM.S90335"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/civ933"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200800353"},{"key":"e_1_3_2_7_2","first-page":"64","article-title":"Invasive fungal infections: a comprehensive review","volume":"1","author":"Ramana KV","year":"2013","unstructured":"Ramana KV KandiSBharatkumarPSharadaCHVRaoRManiRRaoSD. 2013. Invasive fungal infections: a comprehensive review. Am J Infect Dis Microbiol1:64\u201369.","journal-title":"Am J Infect Dis Microbiol"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2006.07.018"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.2165\/11596540-000000000-00000"},{"key":"e_1_3_2_10_2","first-page":"197","article-title":"In search of the Holy Grail of antifungal therapy","volume":"119","author":"Chapman SW","year":"2008","unstructured":"Chapman SW SullivanDCClearyJD. 2008. In search of the Holy Grail of antifungal therapy. Trans Am Clin Climatol Assoc119:197\u2013216.","journal-title":"Trans Am Clin Climatol Assoc"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00185-15"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02770-15"},{"key":"e_1_3_2_13_2","first-page":"45","volume-title":"Novel CYP51 inhibitors for the treatment of coccidioidomycosis","author":"Shubitz LF","year":"2016","unstructured":"Shubitz LF TrinhHRoyMGarveyEPBrandSRHoekstraWJSchotzingerRJ. 2016. Novel CYP51 inhibitors for the treatment of coccidioidomycosis, p 45. Proc 60th Annu Coccidioidomycosis Study Group,Fresno, CA."},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2014.05.068"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03707-14"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00349-16"},{"key":"e_1_3_2_17_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0026-895X(25)14748-2","article-title":"Spectral studies of drug interaction with hepatic microsomal cytochrome","volume":"3","author":"Schenkman JB","year":"1967","unstructured":"Schenkman JB RemmerHEstabrookRW. 1967. Spectral studies of drug interaction with hepatic microsomal cytochrome. Mol Pharmacol3:113\u2013123.","journal-title":"Mol Pharmacol"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.497990"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.677310"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02287-15"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2007.10.011"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.067470"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.778308"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)48462-1"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2014.08.030"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.39.7.2431-2438.2001"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/nph.12193"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msu134"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201510-2104LE"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt508"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiv228"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)82244-3"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M510317200"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444905039107"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444994003112"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889807021206"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10156-002-0201-Y"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00570-17","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00570-17","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T02:43:45Z","timestamp":1750214625000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00570-17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7]]},"references-count":37,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2017,7]]}},"alternative-id":["10.1128\/AAC.00570-17"],"URL":"https:\/\/doi.org\/10.1128\/aac.00570-17","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7]]},"assertion":[{"value":"2017-03-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-04-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-06-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00570-17"}}