{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T03:28:23Z","timestamp":1778642903287,"version":"3.51.4"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p><jats:italic>Candida auris<\/jats:italic> has emerged as a significant healthcare-associated pathogen due to its multidrug-resistant nature. Ongoing constraints in the discovery and provision of new antifungals create an urgent imperative to design effective remedies to this pressing global blight. Herein, we screened a chemical library and identified aryl-carbohydrazide analogs with potent activity against both <jats:italic>C. auris<\/jats:italic> and the most prevalent human fungal pathogen, <jats:italic>C. albicans<\/jats:italic>. SPB00525 [<jats:italic>N<\/jats:italic>\u2019-(2,6-dichlorophenyl)-5-nitro-furan-2-carbohydrazide] exhibited potent activity against different strains that were resistant to standard antifungals. Using drug-induced haploinsufficient profiling, transcriptomics and metabolomic analysis, we uncovered that Ole1, a \u0394(9) fatty acid desaturase, is the likely target of SPB00525. An analog of the latter, HTS06170 [<jats:italic>N<\/jats:italic>\u2019-(2,6-dichlorophenyl)-4-methyl-1,2,3-thiadiazole-5-carbohydrazide], had a superior antifungal activity against both <jats:italic>C. auris<\/jats:italic> and <jats:italic>C. albicans<\/jats:italic>. Both SPB00525 and HTS06170 act as antivirulence agents and inhibited the invasive hyphal growth and biofilm formation of <jats:italic>C. albicans<\/jats:italic>. SPB00525 and HTS06170 attenuated fungal damage to human enterocytes and ameliorate the survival of <jats:italic>Galleria mellonella<\/jats:italic> larvae used as systemic candidiasis model. These data suggest that inhibiting fungal \u0394(9) fatty acid desaturase activity represents a potential therapeutic approach for treating fungal infection caused by the superbug <jats:italic>C. auris<\/jats:italic> and the most prevalent human fungal pathogen, <jats:italic>C. albicans<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fcimb.2024.1434939","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T05:10:58Z","timestamp":1724994658000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Small molecule inhibitors of fungal \u0394(9) fatty acid desaturase as antifungal agents against Candida auris"],"prefix":"10.3389","volume":"14","author":[{"given":"Faiza","family":"Tebbji","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anagha C. T.","family":"Menon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00e8s","family":"Khemiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"St-Cyr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis","family":"Villeneuve","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antony T.","family":"Vincent","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adnane","family":"Sellam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"22044","DOI":"10.1073\/pnas.1009845107","article-title":"Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model","volume":"107","author":"Becker","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B2","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.stem.2012.11.015","article-title":"Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen","volume":"12","author":"Ben-David","year":"2013","journal-title":"Cell Stem Cell"},{"key":"B3","doi-asserted-by":"publisher","first-page":"D711","DOI":"10.1093\/nar\/gkt1046","article-title":"The Candida Genome Database: the new homology information page highlights protein similarity and phylogeny","volume":"42","author":"Binkley","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1002\/yea.1036","article-title":"Protein A-tagging for purification of native macromolecular complexes from Candida albicans","volume":"20","author":"Blackwell","year":"2003","journal-title":"Yeast"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007823","article-title":"A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans","volume":"15","author":"Burgain","year":"2019","journal-title":"PloS Pathog."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00913-19","article-title":"Metabolic reprogramming in the opportunistic yeast candida albicans in response to hypoxia","volume":"5","author":"Burgain","year":"2020","journal-title":"mSphere"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics10040355","article-title":"In Vitro Synergistic Interactions of Isavuconazole and Echinocandins against Candida auris","volume":"10","author":"Caballero","year":"2021","journal-title":"Antibiotics (Basel)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1534\/g3.116.037986","article-title":"Genome-wide screen for haploinsufficient cell size genes in the opportunistic yeast candida albicans","volume":"7","author":"Chaillot","year":"2017","journal-title":"G3 (Bethesda)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.01956","article-title":"pH-Dependant Antifungal Activity of Valproic Acid against the Human Fungal Pathogen Candida albicans","volume":"8","author":"Chaillot","year":"2017","journal-title":"Front. Microbiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"4584","DOI":"10.1128\/AAC.00551-15","article-title":"The monoterpene carvacrol generates endoplasmic reticulum stress in the pathogenic fungus candida albicans","volume":"59","author":"Chaillot","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"B11","doi-asserted-by":"crossref","first-page":"177","DOI":"10.5808\/GI.2010.8.4.177","article-title":"Genomewide Profiling of Rapamycin Sensitivity in Saccharomyces cerevisiae on Synthetic Medium","volume":"8","author":"Chang","year":"2010","journal-title":"Genomics Inf."},{"key":"B12","doi-asserted-by":"publisher","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: an ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006290","article-title":"Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally","volume":"13","author":"Chowdhary","year":"2017","journal-title":"PloS Pathog."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3210","DOI":"10.1021\/acsinfecdis.1c00404","article-title":"Identification of inhibitors of fungal fatty acid biosynthesis","volume":"7","author":"DeJarnette","year":"2021","journal-title":"ACS Infect. Dis."},{"key":"B15","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1111\/j.1462-5822.2008.01259.x","article-title":"Responses to hypoxia in fungal pathogens","volume":"11","author":"Ernst","year":"2009","journal-title":"Cell. Microbiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"11559","DOI":"10.1038\/s41598-018-29973-8","article-title":"A phenotypic small-molecule screen identifies halogenated salicylanilides as inhibitors of fungal morphogenesis, biofilm formation and host cell invasion","volume":"8","author":"Garcia","year":"2018","journal-title":"Sci. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1038\/6791","article-title":"Genomic profiling of drug sensitivities via induced haploinsufficiency","volume":"21","author":"Giaever","year":"1999","journal-title":"Nat. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1002\/yea.1044","article-title":"New modules for PCR-based gene targeting in Candida albicans: rapid and efficient gene targeting using 100 bp of flanking homology region","volume":"20","author":"Gola","year":"2003","journal-title":"Yeast"},{"key":"B20","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/371168a0","article-title":"Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate","volume":"371","author":"Harlan","year":"1994","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/jof6030143","article-title":"Differential regulation of echinocandin targets fks1 and fks2 in candida glabrata by the post-transcriptional regulator ssd1","volume":"6","author":"Healey","year":"2020","journal-title":"J. Fungi"},{"key":"B22","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.micres.2013.11.004","article-title":"High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions","volume":"169","author":"Hoepfner","year":"2014","journal-title":"Microbiological Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.tips.2008.07.006","article-title":"Yeast chemical genomics and drug discovery: an update","volume":"29","author":"Hoon","year":"2008","journal-title":"Trends Pharmacol. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1242\/dmm.005769","article-title":"Combined zebrafish-yeast chemical-genetic screens reveal gene\u2013copper-nutrition interactions that modulate melanocyte pigmentation","volume":"3","author":"Ishizaki","year":"2010","journal-title":"Dis. Models Mech."},{"key":"B25","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.chembiol.2023.06.005","article-title":"Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity","volume":"30","author":"Iyer","year":"2023","journal-title":"Cell Chem. Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"507","DOI":"10.12688\/f1000research.28327.2","article-title":"Novel antifungal agents in clinical trials","volume":"10","author":"Jacobs","year":"2022","journal-title":"F1000Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1128\/jcm.00367-15","article-title":"Multidrug-Resistant Candida auris Misidentified as Candida haemulonii: Characterization by Matrix-Assisted Laser Desorption Ionization\u2013Time of Flight Mass Spectrometry and DNA Sequencing and Its Antifungal Susceptibility Profile Variability by Vitek 2, CLSI Broth Microdilution, and Etest Method","volume":"53","author":"Kathuria","year":"2015","journal-title":"J. Clin. Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1099\/mic.0.27029-0","article-title":"Dosage-dependent functions of fatty acid desaturase Ole1p in growth and morphogenesis of Candida albicans","volume":"150","author":"Krishnamurthy","year":"2004","journal-title":"Microbiology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.2147\/IDR.S375625","article-title":"Novel therapeutic approaches to invasive candidiasis: considerations for the clinician","volume":"16","author":"Lamoth","year":"2023","journal-title":"Infect. Drug Resist."},{"key":"B30","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1093\/cid\/ciw691","article-title":"Simultaneous emergence of multidrug-resistant candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses","volume":"64","author":"Lockhart","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0005-2760(98)00091-5","article-title":"Structure and expression of fatty acid desaturases","volume":"1394","author":"Los","year":"1998","journal-title":"Biochim. Biophys. Acta (BBA) - Lipids Lipid Metab."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.devcel.2012.11.004","article-title":"ER-to-plasma membrane tethering proteins regulate cell signaling and ER morphology","volume":"23","author":"Manford","year":"2012","journal-title":"Dev. Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.bbalip.2006.06.010","article-title":"Regulation of long chain unsaturated fatty acid synthesis in yeast","volume":"1771","author":"Martin","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA) - Mol. Cell Biol. Lipids"},{"key":"B36","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/S0952-3278(02)00261-2","article-title":"Role of stearoyl-coenzyme A desaturase in lipid metabolism","volume":"68","author":"Miyazaki","year":"2003","journal-title":"Prostaglandins Leukotrienes Essential Fatty Acids"},{"key":"B37","doi-asserted-by":"publisher","first-page":"e396","DOI":"10.1016\/S2666-5247(23)00143-X","article-title":"Emergence of resistant Candida auris","volume":"4","author":"Nelson","year":"2023","journal-title":"Lancet Microbe"},{"key":"B38","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1128\/EC.4.2.298-309.2005","article-title":"Strains and strategies for large-scale gene deletion studies of the diploid human fungal pathogen Candida albicans","volume":"4","author":"Noble","year":"2005","journal-title":"Eukaryot Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd7459","article-title":"Mechanisms of stearoyl CoA desaturase inhibitor sensitivity and acquired resistance in cancer","volume":"7","author":"Oatman","year":"2021","journal-title":"Sci. Adv."},{"key":"B40","doi-asserted-by":"publisher","first-page":"E28","DOI":"10.1152\/ajpendo.90897.2008","article-title":"Biochemical and physiological function of stearoyl-CoA desaturase","volume":"297","author":"Paton","year":"2009","journal-title":"Am. J. Physiology-Endocrinology Metab."},{"key":"B41","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1111\/mmi.13738","article-title":"Negative regulation of filamentous growth in Candida albicans by Dig1p","volume":"105","author":"Regan","year":"2017","journal-title":"Mol. Microbiol."},{"key":"B42","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1046\/j.1365-2958.2003.03697.x","article-title":"Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery","volume":"50","author":"Roemer","year":"2003","journal-title":"Mol. Microbiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s13756-016-0132-5","article-title":"First hospital outbreak of the globally emerging Candida auris in a European hospital","volume":"5","author":"Schelenz","year":"2016","journal-title":"Antimicrobial Resistance Infection Control"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"","journal-title":"Nat. Methods"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0043956","article-title":"A novel role for the transcription factor Cwt1p as a negative regulator of nitrosative stress in Candida albicans","volume":"7","author":"Sellam","year":"2012","journal-title":"PloS One"},{"key":"B46","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1128\/EC.00292-13","article-title":"Modeling the transcriptional regulatory network that controls the early hypoxic response in Candida albicans","volume":"13","author":"Sellam","year":"2014","journal-title":"Eukaryot Cell"},{"key":"B47","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/j.trecan.2023.03.003","article-title":"Stearoyl coenzyme A desaturase-1: multitasker in cancer, metabolism, and ferroptosis","volume":"9","author":"Sen","year":"2023","journal-title":"Trends Cancer"},{"key":"B48","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.jmb.2006.06.040","article-title":"Transcriptional response of Candida albicans to hypoxia: linkage of oxygen sensing and Efg1p-regulatory networks","volume":"361","author":"Setiadi","year":"2006","journal-title":"J. Mol. Biol."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0163962","article-title":"SeqKit: A cross-platform and ultrafast toolkit for FASTA\/Q file manipulation","volume":"11","author":"Shen","year":"2016","journal-title":"PloS One"},{"key":"B50","doi-asserted-by":"publisher","first-page":"10.1128\/jcm.01588","DOI":"10.1128\/jcm.01588-17","article-title":"Candida auris: an emerging fungal pathogen","volume":"56","author":"Spivak","year":"2018","journal-title":"J. Clin. Microbiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1128\/EC.00159-10","article-title":"Regulation of the hypoxic response in Candida albicans","volume":"9","author":"Synnott","year":"2011","journal-title":"Eukaryot Cell"},{"key":"B52","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1080\/14756366.2022.2050224","article-title":"Echinocandins \u2013 structure, mechanism of action and use in antifungal therapy","volume":"37","author":"Szyma\u0144ski","year":"2022","journal-title":"J. Enzyme Inhibition Medicinal Chem."},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004770","article-title":"A functional portrait of med7 and the mediator complex in candida albicans","volume":"10","author":"Tebbji","year":"2014","journal-title":"PloS Genet."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/jof8111144","article-title":"Recent Antifungal Pipeline Developments against Candida auris: A Systematic Review","volume":"8","author":"Trevi\u00f1o-Rangel","year":"2022","journal-title":"J. Fungi (Basel)"},{"key":"B55","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1111\/jhn.12272","article-title":"Validation of fatty acid intakes estimated by a food frequency questionnaire using erythrocyte fatty acid profiling in the Montreal Heart Institute Biobank","volume":"28","author":"Turcot","year":"2015","journal-title":"J. Hum. Nutr. Dietetics"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.micres.2023.127517","article-title":"Update on fungal lipid biosynthesis inhibitors as antifungal agents","volume":"278","author":"Vishwakarma","year":"2024","journal-title":"Microbiological Res."},{"key":"B57","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1111\/myc.13049","article-title":"Candida biofilm production is associated with higher mortality in patients with candidaemia","volume":"63","author":"Vit\u00e1lis","year":"2020","journal-title":"Mycoses"},{"key":"B58","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.fgb.2009.09.003","article-title":"Fungal echinocandin resistance","volume":"47","author":"Walker","year":"2010","journal-title":"Fungal Genet. Biol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"160095","DOI":"10.1038\/sdata.2016.95","article-title":"Systematic chemical-genetic and chemical-chemical interaction datasets for prediction of compound synergism","volume":"3","author":"Wildenhain","year":"2016","journal-title":"Sci. Data"},{"key":"B60","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.chembiol.2012.12.008","article-title":"A yeast chemical genetic screen identifies inhibitors of human telomerase","volume":"20","author":"Wong","year":"2013","journal-title":"Chem. Biol."},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0030092","article-title":"Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albicans","volume":"3","author":"Xu","year":"2007","journal-title":"PloS Pathog."},{"key":"B62","doi-asserted-by":"publisher","first-page":"19754","DOI":"10.1074\/jbc.M109.019877","article-title":"Chemical genetic profiling and characterization of small-molecule compounds that affect the biosynthesis of unsaturated fatty acids in candida albicans*","volume":"284","author":"Xu","year":"2009","journal-title":"J. Biol. Chem."},{"key":"B63","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1080\/15384047.2021.1883414","article-title":"NF-\u03baB pathway play a role in SCD1 deficiency-induced ceramide de novo synthesis","volume":"22","author":"Zheng","year":"2021","journal-title":"Cancer Biol. Ther."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2024.1434939\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T05:11:04Z","timestamp":1724994664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2024.1434939\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,30]]},"references-count":63,"alternative-id":["10.3389\/fcimb.2024.1434939"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2024.1434939","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,30]]},"article-number":"1434939"}}