{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:47:53Z","timestamp":1789512473585,"version":"build-2803163510"},"reference-count":79,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Canadian Government | Natural Sciences and Engineering Research Council of Canada","award":["2024-06684"],"award-info":[{"award-number":["2024-06684"]}]},{"DOI":"10.13039\/501100000106","name":"Saskatchewan Health Research Foundation","doi-asserted-by":"crossref","award":["4769"],"award-info":[{"award-number":["4769"]}],"id":[{"id":"10.13039\/501100000106","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Canadian Government | Natural Sciences and Engineering Research Council of Canada","award":["2018-06649"],"award-info":[{"award-number":["2018-06649"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2025,3,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              <jats:italic>Candida albicans<\/jats:italic>\n              typically thrives in a commensal relationship with humans but is also an opportunistic fungal pathogen. As an opportunistic pathogen,\n              <jats:italic>C. albicans<\/jats:italic>\n              relies heavily on its ability to assimilate nutrients, for which it must compete with the host and other microorganisms. Amino acid biosynthesis, sensing, and uptake play pivotal roles in\n              <jats:italic>C. albicans<\/jats:italic>\n              growth and pathogenicity.\n              <jats:italic>C. albicans<\/jats:italic>\n              biosynthesizes aromatic amino acids and co-enzyme Q\n              <jats:italic>de novo<\/jats:italic>\n              through the shikimate pathway, including the Aro1, Aro2, and Aro7 enzymes, but also has amino acid transporters for uptake from the environment. Thus, antifungal approaches targeting aromatic amino acid biosynthesis must simultaneously inhibit amino acid biosynthesis and uptake. Herein, we investigate the plant-based antifungal, carvacrol, in conjunction with aromatic amino acid biosynthetic mutants, as a potential anti-candidal strategy. Growth of the WT,\n              <jats:italic>ARO2<\/jats:italic>\n              , and\n              <jats:italic>ARO7<\/jats:italic>\n              strains were inhibited by 150 \u00b5g\/mL carvacrol, whereas the\n              <jats:italic>ARO1<\/jats:italic>\n              mutant was slightly more sensitive (with MIC 125 \u00b5g\/mL). All repressed mutants exposed to carvacrol are partially rescued in the presence of para-aminobenzoic acid (PABA) (CoQ precursor), indicating that blocking the shikimate pathway impacts both aromatic amino acid and CoQ biosynthesis. Moreover, carvacrol at sublethal concentrations significantly inhibits\n              <jats:italic>ARO1<\/jats:italic>\n              adhesion and hyphal formation, along with pre-attached and pre-formed hyphae, ultimately impacting biofilm metabolic activity and biomass accumulation and significantly reducing biofilm growth. In summary, carvacrol increases the sensitivity of\n              <jats:italic>C. albicans<\/jats:italic>\n              to\n              <jats:italic>ARO1<\/jats:italic>\n              repression, with attenuated adhesion, hyphal formation, mycelial growth and biofilm formation, likely by blocking aromatic amino acid uptake.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                The opportunistic pathogen\n                <jats:italic>Candida albicans<\/jats:italic>\n                remains the leading cause of candidemia and invasive candidiasis (IC), causing significant morbidity and mortality in immunocompromised patients. Our current arsenal of effective antifungal drugs is limited in number, mechanistic diversity, and efficacy, are cytotoxic and associated with antifungal resistance, necessitating the development of novel antifungals and combination therapies. Here, we show how simultaneously blocking the shikimate pathway, through\n                <jats:italic>ARO1<\/jats:italic>\n                repression, and disrupting aromatic amino acid uptake by carvacrol prevent\n                <jats:italic>C. albicans<\/jats:italic>\n                biofilm formation. Thus, inhibitors of the Aro1 enzyme in combination with carvacrol are expected to shut down\n                <jats:italic>C. albicans<\/jats:italic>\n                biofilm formation and virulence.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.02754-24","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T14:00:43Z","timestamp":1738936843000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Blocking the shikimate pathway amplifies the impact of carvacrol on biofilm formation in\n            <i>Candida albicans<\/i>"],"prefix":"10.1128","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6776-5214","authenticated-orcid":false,"given":"Ali","family":"Molaeitabari","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Regina","place":["Regina, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8378-7480","authenticated-orcid":false,"given":"Tanya E. S.","family":"Dahms","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Regina","place":["Regina, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/jof3040057"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004404"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/1469-0691.12539"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinmicnews.2014.08.001"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.26"},{"key":"e_1_3_3_7_2","first-page":"3","volume-title":"Candida albicans","author":"Yang B","year":"2019","unstructured":"Yang B, Rao R. 2019. Emerging pathogens of the Candida species, p 3\u201318. In Candida albicans"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mycmed.2019.07.006"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12275-016-5514-0"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-020-03912-w"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.2144\/fsoa-2019-0027"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/jam.14949"},{"key":"e_1_3_3_13_2","unstructured":"Hameed AR Ali SM Ahmed L. 2018. Biological study of Candida species and virulence factor. International Journal of Advanced Research in Engineering & Technology"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.4161\/viru.22913"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms8060857"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2016.01.002"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2014.07.001"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.27121-0"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.4161\/viru.20010"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a019695"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202101358"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmii.2018.04.002"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-021-03007-6"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-014-1873-1"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12934-016-0485-8"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.151894"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2015.12.007"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7741"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02048-18"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00284-16"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00192"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2475"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17625"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2008.06.034"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.14.10.6597-6606.1994"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens11010005"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40588-019-00124-5"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.05026-11"},{"key":"e_1_3_3_39_2","unstructured":"Centers US Control D. 2019. Antibiotic resistance threats in the United States"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.4014\/jmb.1807.07002"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.3109\/15569527.2015.1020544"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.655327"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2013.12.057"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.3390\/ph10040086"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-010-1050-8"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1023\/a:1013311632207"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1080\/10412905.2012.754728"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13596-020-00482-2"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.23893\/1307-2080.APS.05811"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-302X.2004.00202.x"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms7100378"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00551-15"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2006.06.018"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2016.1188236"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11122915"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076028"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-45624-y"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03697.x"},{"key":"e_1_3_3_59_2","volume-title":"Reference method for broth dilution antifungal susceptibility testing; approved standard","author":"Clinical and Laboratory Standards Institute (CLSI)","year":"2008","unstructured":"Clinical and Laboratory Standards Institute (CLSI). 2008. Reference method for broth dilution. In Reference method for broth dilution antifungal susceptibility testing; approved standard. https:\/\/clsi.org\/media\/1461\/m27a3_sample.pdf."},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2012.01813.x"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms10101989"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0277097"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02749-16"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00127-13"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1567-1364.2009.00541.x"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2009.01412.x"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000294"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.2.6.1266-1273.2003"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0966-842x(01)01984-9"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.05085-11"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2636"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2006.00761.x"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0020063"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2006.10.003"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1093\/femsyr\/fov027"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1087-1845(02)00007-5"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.06.040"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1305982110"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00526-12"},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.05184-11"}],"container-title":["Microbiology Spectrum"],"original-title":[],"contributor":[{"given":"Alireza","family":"Khodavandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"reviewer"}]}],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.02754-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.02754-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T14:03:02Z","timestamp":1741096982000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/spectrum.02754-24"}},"subtitle":[],"editor":[{"given":"Renato","family":"Kovacs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":79,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3,4]]}},"alternative-id":["10.1128\/spectrum.02754-24"],"URL":"https:\/\/doi.org\/10.1128\/spectrum.02754-24","relation":{},"ISSN":["2165-0497"],"issn-type":[{"value":"2165-0497","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,4]]},"assertion":[{"value":"2024-11-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02754-24"}}