{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T02:36:01Z","timestamp":1790562961035,"version":"4.1.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T00:00:00Z","timestamp":1608595200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T00:00:00Z","timestamp":1608595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI141202"],"award-info":[{"award-number":["R01AI141202"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI073289"],"award-info":[{"award-number":["R01AI073289"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["GM111615"],"award-info":[{"award-number":["GM111615"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["GM118173"],"award-info":[{"award-number":["GM118173"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Candida auris<\/jats:italic> is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a <jats:italic>bis<\/jats:italic>-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against <jats:italic>C. auris<\/jats:italic>. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most <jats:italic>C. auris<\/jats:italic> clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of <jats:italic>Candida albicans<\/jats:italic>, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with <jats:italic>C. auris<\/jats:italic>, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of <jats:italic>C. auris<\/jats:italic>.<\/jats:p>","DOI":"10.1038\/s41467-020-20183-3","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T11:03:02Z","timestamp":1608634982000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris"],"prefix":"10.1038","volume":"11","author":[{"given":"Kali R.","family":"Iyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaddy","family":"Camara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Daniel-Ivad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Trilles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila M.","family":"Pimentel-Elardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen L.","family":"Fossen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Marchillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongle","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakti","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4987-7957","authenticated-orcid":false,"given":"Jos\u00e9 F.","family":"Mu\u00f1oz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0597-0623","authenticated-orcid":false,"given":"Sang Hu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2991-5680","authenticated-orcid":false,"suffix":"Jr.","given":"John A.","family":"Porco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5778-960X","authenticated-orcid":false,"given":"Christina A.","family":"Cuomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelle S.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3787-8530","authenticated-orcid":false,"given":"Ashraf S.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"John E.","family":"Edwards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Andes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7909-1803","authenticated-orcid":false,"given":"Justin R.","family":"Nodwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9489-484X","authenticated-orcid":false,"given":"Lauren E.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Whitesell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Robbins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5797-0110","authenticated-orcid":false,"given":"Leah E.","family":"Cowen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,22]]},"reference":[{"key":"20183_CR1","doi-asserted-by":"publisher","DOI":"10.1596\/26707","volume-title":"Drug-Resistant Infections: A Threat To Our Economic Future","author":"World Bank.","year":"2017","unstructured":"World Bank. Drug-Resistant Infections: A Threat To Our Economic Future. (World Bank. License: Creative Commons Attribution CC BY 3.0 IGO, Washington, DC, 2017)."},{"key":"20183_CR2","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1056\/NEJMoa1714373","volume":"379","author":"DW Eyre","year":"2018","unstructured":"Eyre, D. W. et al. A Canida auris outbreak and its control in an intensive care setting. New Engl. J. Med. 379, 1322\u20131331 (2018).","journal-title":"New Engl. J. Med."},{"key":"20183_CR3","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1093\/cid\/ciw691","volume":"64","author":"SR Lockhart","year":"2017","unstructured":"Lockhart, S. R. et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin. Infect. Dis. 64, 134\u2013140 (2017).","journal-title":"Clin. Infect. Dis."},{"key":"20183_CR4","unstructured":"Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States (U.S. Department of Health and Human Services, 2019)."},{"key":"20183_CR5","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1111\/j.1348-0421.2008.00083.x","volume":"53","author":"K Satoh","year":"2009","unstructured":"Satoh, K. et al. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiol. Immunol. 53, 41\u201344 (2009).","journal-title":"Microbiol. Immunol."},{"key":"20183_CR6","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.mib.2019.05.008","volume":"52","author":"J Rhodes","year":"2019","unstructured":"Rhodes, J. & Fisher, M. C. Global epidemiology of emerging Candida auris. Curr. Opin. Microbiol. 52, 84\u201389 (2019).","journal-title":"Curr. Opin. Microbiol."},{"key":"20183_CR7","doi-asserted-by":"publisher","first-page":"e03364","DOI":"10.1128\/mBio.03364-19","volume":"11","author":"N Chow","year":"2020","unstructured":"Chow, N. et al. Tracing the evolutionary history and global expansion of Candida auris using population genomic analyses. mBio 11, e03364\u201319 (2020).","journal-title":"mBio"},{"key":"20183_CR8","doi-asserted-by":"crossref","unstructured":"Schelenz, S. et al. First hospital outbreak of the globally emerging Candida auris in a European hospital. Antimicrob. Resist. Infect. Control 5, 35 (2016).","DOI":"10.1186\/s13756-016-0132-5"},{"key":"20183_CR9","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1111\/myc.12781","volume":"61","author":"A Ruiz-Gait\u00e1n","year":"2018","unstructured":"Ruiz-Gait\u00e1n, A. et al. An outbreak due to Candida auris with prolonged colonisation and candidaemia in a tertiary care European hospital. Mycoses 61, 498\u2013505 (2018).","journal-title":"Mycoses"},{"key":"20183_CR10","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1146\/annurev-micro-030117-020345","volume":"71","author":"N Robbins","year":"2017","unstructured":"Robbins, N., Caplan, T. & Cowen, L. E. Molecular evolution of antifungal drug resistance. Annu. Rev. Microbiol. 71, 753\u2013775 (2017).","journal-title":"Annu. Rev. Microbiol."},{"key":"20183_CR11","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.mib.2018.02.005","volume":"45","author":"NM Revie","year":"2018","unstructured":"Revie, N. M., Iyer, K. R., Robbins, N. & Cowen, L. E. Antifungal drug resistance: evolution, mechanisms and impact. Curr. Opin. Microbiol. 45, 70\u201376 (2018).","journal-title":"Curr. Opin. Microbiol."},{"key":"20183_CR12","doi-asserted-by":"publisher","first-page":"4527","DOI":"10.1128\/AAC.00348-10","volume":"54","author":"CM Martel","year":"2010","unstructured":"Martel, C. M. et al. Identification and characterization of four azole-resistant ERG3 mutants of Candida albicans. Antimicrob. Agents Chemother. 54, 4527\u20134533 (2010).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR13","doi-asserted-by":"publisher","first-page":"4233","DOI":"10.1128\/AAC.06332-11","volume":"56","author":"D Hoepfner","year":"2012","unstructured":"Hoepfner, D. et al. An integrated approach for identification and target validation of antifungal compounds active against Erg11p. Antimicrob. Agents Chemother. 56, 4233\u20134240 (2012).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR14","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1128\/AAC.03470-14","volume":"59","author":"SA Flowers","year":"2015","unstructured":"Flowers, S. A., Col\u00f3n, B., Whaley, S. G., Schuler, M. A. & David Rogers, P. Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans. Antimicrob. Agents Chemother. 59, 450\u2013460 (2015).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR15","doi-asserted-by":"publisher","first-page":"2676","DOI":"10.1128\/AAC.45.10.2676-2684.2001","volume":"45","author":"S Perea","year":"2001","unstructured":"Perea, S. et al. Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 45, 2676\u20132684 (2001).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR16","doi-asserted-by":"publisher","first-page":"e01427-18","DOI":"10.1128\/AAC.01427-18","volume":"62","author":"KR Healey","year":"2018","unstructured":"Healey, K. R. et al. Limited ERG11 mutations identified in isolates of Candida auris directly contribute to reduced azole susceptibility. Antimicrob. Agents Chemother. 62, e01427-18 (2018).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR17","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.3389\/fmicb.2019.01445","volume":"10","author":"M Wasi","year":"2019","unstructured":"Wasi, M. et al. ABC transporter genes show upregulated expression in drug-resistant clinical isolates of Candida auris: a genome-wide characterization of ATP-binding cassette (ABC) transporter genes. Front. Microbiol. 10, 1445 (2019).","journal-title":"Front. Microbiol."},{"key":"20183_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07779-6","volume":"9","author":"JF Mu\u00f1oz","year":"2018","unstructured":"Mu\u00f1oz, J. F. et al. Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species. Nat. Commun. 9, 5346 (2018).","journal-title":"Nat. Commun."},{"key":"20183_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/mSphere.00334-18","volume":"3","author":"R Kean","year":"2018","unstructured":"Kean, R. et al. Transcriptome assembly and profiling of Candida auris reveals novel insights into biofilm-mediated resistance. mSphere 3, 1\u201314 (2018).","journal-title":"mSphere"},{"key":"20183_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/AAC.00057-19","volume":"63","author":"JM Rybak","year":"2019","unstructured":"Rybak, J. M. et al. Abrogation of triazole resistance upon deletion of CDR1 in a clinical isolate of Candida auris. Antimicrob. Agents Chemother. 63, 1\u20137 (2019).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR21","doi-asserted-by":"publisher","first-page":"e00365","DOI":"10.1128\/mBio.00365-20","volume":"11","author":"JM Rybak","year":"2020","unstructured":"Rybak, J. M. et al. Mutations in\u00a0TAC1B: a novel genetic determinant of clinical fluconazole resistance in\u00a0Candida auris.\u00a0mBio\u00a011, e00365\u201320 (2020).","journal-title":"mBio"},{"key":"20183_CR22","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1016\/j.ijantimicag.2018.08.016","volume":"52","author":"HE Eldesouky","year":"2018","unstructured":"Eldesouky, H. E., Li, X., Abutaleb, N. S., Mohammad, H. & Seleem, M. N. Synergistic interactions of sulfamethoxazole and azole antifungal drugs against emerging multidrug-resistant Candida auris. Int. J. Antimicrob. Agents 52, 754\u2013761 (2018).","journal-title":"Int. J. Antimicrob. Agents"},{"key":"20183_CR23","first-page":"e02195","volume":"64","author":"B O\u2019Brien","year":"2020","unstructured":"O\u2019Brien, B., Chaturvedi, S. & Chaturvedi, V. In vitro evaluation of antifungal drug combinations against multidrug-resistant Candida auris isolates from New York outbreak. Antimicrob. Agents Chemother. 64, e02195\u201319 (2020).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR24","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/nature16963","volume":"530","author":"JL Nishikawa","year":"2016","unstructured":"Nishikawa, J. L. et al. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature 530, 485\u2013489 (2016).","journal-title":"Nature"},{"key":"20183_CR25","doi-asserted-by":"publisher","first-page":"165rv13","DOI":"10.1126\/scitranslmed.3004404","volume":"4","author":"GD Brown","year":"2012","unstructured":"Brown, G. D. et al. Hidden killers: human fungal infections. Sci. Transl. Med. 4, 165rv13 (2012).","journal-title":"Sci. Transl. Med."},{"key":"20183_CR26","doi-asserted-by":"publisher","first-page":"6775","DOI":"10.1073\/pnas.1017666108","volume":"108","author":"LE Brown","year":"2011","unstructured":"Brown, L. E. et al. Discovery of new antimalarial chemotypes through chemical methodology and library development. Proc. Natl Acad. Sci. USA 108, 6775\u20136780 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"20183_CR27","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.chembiol.2011.01.009","volume":"18","author":"T Roemer","year":"2011","unstructured":"Roemer, T. et al. Confronting the challenges of natural product-based antifungal discovery. Chem. Biol. 18, 148\u2013164 (2011).","journal-title":"Chem. Biol."},{"key":"20183_CR28","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/nrd.2017.46","volume":"16","author":"JR Perfect","year":"2017","unstructured":"Perfect, J. R. The antifungal pipeline: a reality check. Nat. Rev. Drug Discov. 16, 603\u2013616 (2017).","journal-title":"Nat. Rev. Drug Discov."},{"key":"20183_CR29","doi-asserted-by":"publisher","first-page":"e03329","DOI":"10.1128\/mBio.03329-19","volume":"11","author":"KR Iyer","year":"2020","unstructured":"Iyer, K. R. et al. Translation inhibition by rocaglates activates a species- specific cell death program in the emerging fungal pathogen Candida auris. mBio 11, e03329\u201319 (2020).","journal-title":"mBio"},{"key":"20183_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jac\/dkg301","volume":"52","author":"FC Odds","year":"2003","unstructured":"Odds, F. C. Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 52, 1 (2003).","journal-title":"J. Antimicrob. Chemother."},{"key":"20183_CR31","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1080\/21505594.2016.1196300","volume":"8","author":"M Spitzer","year":"2016","unstructured":"Spitzer, M., Robbins, N. & Wright, G. D. Combinatorial strategies for combating invasive fungal infections. Virulence 8, 169\u2013185 (2016).","journal-title":"Virulence"},{"key":"20183_CR32","doi-asserted-by":"publisher","first-page":"e1000925","DOI":"10.1371\/journal.pcbi.1000925","volume":"6","author":"M Iskar","year":"2010","unstructured":"Iskar, M. et al. Drug-induced regulation of target expression. PLoS Comput. Biol. 6, e1000925 (2010).","journal-title":"PLoS Comput. Biol."},{"key":"20183_CR33","doi-asserted-by":"publisher","first-page":"2693","DOI":"10.1128\/AAC.44.10.2693-2700.2000","volume":"44","author":"KW Henry","year":"2000","unstructured":"Henry, K. W., Nickels, J. T. & Edlind, T. D. Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors. Antimicrob. Agents Chemother. 44, 2693\u20132700 (2000).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR34","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.ab.2009.07.001","volume":"394","author":"I Ivnitski-Steele","year":"2009","unstructured":"Ivnitski-Steele, I. et al. Identification of Nile red as a fluorescent substrate of the Candida albicans ATP-binding cassette transporters Cdr1p and Cdr2p and the major facilitator superfamily transporter Mdr1p. Anal. Biochem. 394, 87\u201391 (2009).","journal-title":"Anal. Biochem."},{"key":"20183_CR35","first-page":"e02529","volume":"10","author":"SH Kim","year":"2019","unstructured":"Kim, S. H. et al. Genetic analysis of Candida auris implicates Hsp90 in morphogenesis and azole tolerance and Cdr1 in azole resistance. mBio 10, e02529\u201318 (2019).","journal-title":"mBio"},{"key":"20183_CR36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4061\/2011\/531412","volume":"2011","author":"R Prasad","year":"2011","unstructured":"Prasad, R., Sharma, M. & Rawal, M. K. Functionally relevant residues of Cdr1p: a multidrug ABC transporter of human pathogenic Candida albicans. J. Amino Acids 2011, 1\u201312 (2011).","journal-title":"J. Amino Acids"},{"key":"20183_CR37","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1093\/jac\/dki088","volume":"55","author":"VMS Copping","year":"2005","unstructured":"Copping, V. M. S. et al. Exposure of Candida albicans to antifungal agents affects expression of SAP2 and SAP9 secreted proteinase genes. J. Antimicrob. Chemother. 55, 645\u2013654 (2005).","journal-title":"J. Antimicrob. Chemother."},{"key":"20183_CR38","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1021\/id5000212","volume":"1","author":"PA Mann","year":"2015","unstructured":"Mann, P. A. et al. Chemical genomics-based antifungal drug discovery: targeting glycosylphosphatidylinositol (GPI) precursor biosynthesis. ACS Infect. Dis. 1, 59\u201372 (2015).","journal-title":"ACS Infect. Dis."},{"key":"20183_CR39","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.4155\/fmc-2016-0050","volume":"8","author":"AR Holmes","year":"2016","unstructured":"Holmes, A. R. et al. Targeting efflux pumps to overcome antifungal drug resistance. Future Med. Chem. 8, 1485\u20131501 (2016).","journal-title":"Future Med. Chem."},{"key":"20183_CR40","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1128\/AAC.41.7.1482","volume":"41","author":"TC White","year":"1997","unstructured":"White, T. C. Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob. Agents Chemother. 41, 1482\u20131487 (1997).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR41","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1371\/journal.ppat.0030164","volume":"3","author":"J Morschh\u00e4user","year":"2007","unstructured":"Morschh\u00e4user, J. et al. The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog. 3, e164 (2007).","journal-title":"PLoS Pathog."},{"key":"20183_CR42","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1128\/AAC.41.7.1488","volume":"41","author":"TC White","year":"1997","unstructured":"White, T. C. The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14\u03b1 demethylase in Candida albicans. Antimicrob. Agents Chemother. 41, 1488\u20131494 (1997).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR43","doi-asserted-by":"publisher","first-page":"S102","DOI":"10.1111\/j.1601-0825.1997.tb00336.x","volume":"3","author":"TC White","year":"1997","unstructured":"White, T. C., Pfaller, M. A., Rinaldi, M., Smith, J. & Redding, S. Stable azole drug resistance associated with a substrain of Candida albicans from an HIV\u2010infected patient. Oral Dis. 3, S102 (1997).","journal-title":"Oral Dis."},{"key":"20183_CR44","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.celrep.2015.01.009","volume":"10","author":"JA Hill","year":"2015","unstructured":"Hill, J. A., O\u2019Meara, T. R. & Cowen, L. E. Fitness trade-offs associated with the evolution of resistance to antifungal drug combinations. Cell Rep. 10, 809\u2013819 (2015).","journal-title":"Cell Rep."},{"key":"20183_CR45","doi-asserted-by":"publisher","first-page":"e00584","DOI":"10.1128\/AAC.00584-17","volume":"61","author":"C Popp","year":"2017","unstructured":"Popp, C. et al. Competitive fitness of fluconazole- resistant clinical Candida albicans strains. Antimicrob. Agents Chemother. 61, e00584\u201317 (2017).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR46","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1128\/EC.00069-09","volume":"8","author":"AT Coste","year":"2009","unstructured":"Coste, A. T., Crittin, J., Bauser, C., Rohde, B. & Sanglard, D. Functional analysis of cis-and trans-acting elements of the Candida albicans CDR2 promoter with a novel promoter reporter system. Eukaryot. Cell 8, 1250\u20131267 (2009).","journal-title":"Eukaryot. Cell"},{"key":"20183_CR47","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.chembiol.2019.12.008","volume":"27","author":"T Caplan","year":"2020","unstructured":"Caplan, T. et al. Overcoming fungal echinocandin resistance through inhibition of the non-essential stress kinase Yck2. Cell Chem. Biol. 27, 269\u2013282.e5 (2020).","journal-title":"Cell Chem. Biol."},{"key":"20183_CR48","first-page":"e00899","volume":"64","author":"S Liston","year":"2020","unstructured":"Liston, S. et al. Antifungal activity of gepinacin-scaffold GPI anchor biosynthesis inhibitors with improved metabolic stability. Antimicrob. Agents Chemother. 64, e00899\u201320 (2020).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR49","first-page":"e00791","volume":"61","author":"AJ Lepak","year":"2017","unstructured":"Lepak, A. J., Zhao, M., Berkow, E. L., Lockhart, S. R. & Andes, D. R. Pharmacodynamic optimization for treatment of invasive Candida auris infection. Antimicrob. Agents Chemother. 61, e00791\u201317 (2017).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR50","doi-asserted-by":"publisher","first-page":"e17589","DOI":"10.1371\/journal.pone.0017589","volume":"6","author":"S Ferrari","year":"2011","unstructured":"Ferrari, S., Sanguinetti, M., Torelli, R., Posteraro, B. & Sanglard, D. Contribution of CgPDR1-regulated genes in enhanced virulence of azole-resistant Candida glabrata. PLoS ONE 6, e17589 (2011).","journal-title":"PLoS ONE"},{"key":"20183_CR51","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/S0925-4439(02)00087-X","volume":"1587","author":"J Morschh\u00e4user","year":"2002","unstructured":"Morschh\u00e4user, J. The genetic basis of fluconazole resistance development in Candida albicans. Biochim. Biophys. Acta 1587, 240\u2013248 (2002).","journal-title":"Biochim. Biophys. Acta"},{"key":"20183_CR52","first-page":"129","volume":"149","author":"A Sharma","year":"2019","unstructured":"Sharma, A., Gupta, V. & Pathania, R. Efflux pump inhibitors for bacterial pathogens: from bench to bedside. Indian J. Med. Res. 149, 129 (2019).","journal-title":"Indian J. Med. Res."},{"key":"20183_CR53","doi-asserted-by":"publisher","first-page":"2990","DOI":"10.3389\/fmicb.2018.02990","volume":"9","author":"V Shriram","year":"2018","unstructured":"Shriram, V., Khare, T., Bhagwat, R., Shukla, R. & Kumar, V. Inhibiting bacterial drug efflux pumps via phyto-therapeutics to combat threatening antimicrobial resistance. Front. Microbiol. 9, 2990 (2018).","journal-title":"Front. Microbiol."},{"key":"20183_CR54","doi-asserted-by":"publisher","first-page":"3362","DOI":"10.1021\/ol901201k","volume":"11","author":"MP Castaldi","year":"2009","unstructured":"Castaldi, M. P., Troast, D. M. & Porco, J. Jr. Stereoselective synthesis of spirocyclic oxindoles via prins cyclizations. Org. Lett. 11, 3362\u20133365 (2009).","journal-title":"Org. Lett."},{"key":"20183_CR55","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1002\/cam4.107","volume":"2","author":"BL Morrison","year":"2013","unstructured":"Morrison, B. L. et al. Oxyphenisatin acetate (NSC 59687) triggers a cell starvation response leading to autophagy, mitochondrial dysfunction, and autocrine TNF\u03b1-mediated apoptosis. Cancer Med. 2, 687\u2013700 (2013).","journal-title":"Cancer Med."},{"key":"20183_CR56","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.ejmech.2013.08.030","volume":"69","author":"S Denoyelle","year":"2013","unstructured":"Denoyelle, S. et al. Synthesis and SAR study of novel 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as potent eIF2\u00b7GTP\u00b7Met-tRNAiMet ternary complex inhibitors. Eur. J. Med. Chem. 69, 537\u2013553 (2013).","journal-title":"Eur. J. Med. Chem."},{"key":"20183_CR57","doi-asserted-by":"publisher","first-page":"14741","DOI":"10.18632\/oncotarget.10819","volume":"9","author":"X Zheng","year":"2018","unstructured":"Zheng, X. et al. Targeting multidrug-resistant ovarian cancer through estrogen receptor a dependent ATP depletion caused by hyperactivation of the unfolded protein response. Oncotarget 9, 14741\u201314753 (2018).","journal-title":"Oncotarget"},{"key":"20183_CR58","doi-asserted-by":"publisher","first-page":"2553","DOI":"10.1016\/j.bmcl.2005.03.086","volume":"15","author":"DA Neel","year":"2005","unstructured":"Neel, D. A. et al. 3,3-Bisaryloxindoles as mineralocorticoid receptor antagonists. Bioorg. Med. Chem. Lett. 15, 2553\u20132557 (2005).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"20183_CR59","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1016\/j.ejmech.2009.12.035","volume":"45","author":"A Andreani","year":"2010","unstructured":"Andreani, A. et al. New isatin derivatives with antioxidant activity. Eur. J. Med. Chem. 45, 1374\u20131378 (2010).","journal-title":"Eur. J. Med. Chem."},{"key":"20183_CR60","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1007\/BF00352101","volume":"27","author":"R Prasad","year":"1995","unstructured":"Prasad, R., De Wergifosse, P., Goffeau, A. & Balzi, E. Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals. Curr. Genet. 27, 320\u2013329 (1995).","journal-title":"Curr. Genet."},{"key":"20183_CR61","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.cels.2019.09.009","volume":"10","author":"A Celaj","year":"2020","unstructured":"Celaj, A. et al. Highly combinatorial genetic interaction analysis reveals a multi-drug transporter influence network. Cell Syst. 10, 25\u201338.e10 (2020).","journal-title":"Cell Syst."},{"key":"20183_CR62","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1128\/AAC.00926-08","volume":"53","author":"S Tsao","year":"2009","unstructured":"Tsao, S., Rahkhoodaee, F. & Raymond, M. Relative contributions of the Candida albicans ABC transporters Cdr1p and Cdr2p to clinical azole resistance. Antimicrob. Agents Chemother. 53, 1344\u20131352 (2009).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR63","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1016\/j.bcp.2005.12.008","volume":"71","author":"O Lomovskaya","year":"2006","unstructured":"Lomovskaya, O. & Bostian, K. A. Practical applications and feasibility of efflux pump inhibitors in the clinic - a vision for applied use. Biochem. Pharmacol. 71, 910\u2013918 (2006).","journal-title":"Biochem. Pharmacol."},{"key":"20183_CR64","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1038\/nchembio.2165","volume":"12","author":"T Shekhar-Guturja","year":"2016","unstructured":"Shekhar-Guturja, T. et al. Dual action antifungal small molecule modulates multidrug efflux and TOR signaling. Nat. Chem. Biol. 12, 867\u2013875 (2016).","journal-title":"Nat. Chem. Biol."},{"key":"20183_CR65","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.synbio.2016.10.001","volume":"1","author":"Y Tong","year":"2016","unstructured":"Tong, Y. et al. Beauvericin counteracted multi-drug resistant Candida albicans by blocking ABC transporters. Synth. Syst. Biotechnol. 1, 158\u2013168 (2016).","journal-title":"Synth. Syst. Biotechnol."},{"key":"20183_CR66","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/s41568-018-0005-8","volume":"18","author":"RW Robey","year":"2018","unstructured":"Robey, R. W. et al. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat. Rev. Cancer 18, 452\u2013464 (2018).","journal-title":"Nat. Rev. Cancer"},{"key":"20183_CR67","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.tim.2016.06.009","volume":"24","author":"GD Wright","year":"2016","unstructured":"Wright, G. D. Antibiotic adjuvants: rescuing antibiotics from resistance. Trends Microbiol. 24, 862\u2013871 (2016).","journal-title":"Trends Microbiol."},{"key":"20183_CR68","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/mSphere.00130-16","volume":"1","author":"K Min","year":"2016","unstructured":"Min, K., Ichikawa, Y., Woolford, C. A. & Mitchell, A. P. Candida albicans gene deletion with a transient CRISPR-Cas9 system. mSphere 1, 1\u20139 (2016).","journal-title":"mSphere"},{"key":"20183_CR69","first-page":"1","volume":"61","author":"Z Liu","year":"2017","unstructured":"Liu, Z. & Myers, L. C. Mediator tail module is required for Tac1-activated CDR1 expression and azole resistance in Candida albicans. Antimicrob. Agents Chemother. 61, 1\u201320 (2017).","journal-title":"Antimicrob. Agents Chemother."},{"key":"20183_CR70","doi-asserted-by":"crossref","unstructured":"Homann, O. R., Dea, J., Noble, S. M. & Johnson, A. D. A phenotypic profile of the Candida albicans regulatory network. PLoS Genet. 5, e1000783 (2009).","DOI":"10.1371\/journal.pgen.1000783"},{"key":"20183_CR71","doi-asserted-by":"publisher","first-page":"e252","DOI":"10.21769\/BioProtoc.252","volume":"2","author":"J Xie","year":"2012","unstructured":"Xie, J., Singh-Babak, S. & Cowen, L. Minimum inhibitory concentration (MIC) assay for antifungal drugs. Bio-Protocol 2, e252 (2012).","journal-title":"Bio-Protocol"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-020-20183-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-020-20183-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-020-20183-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T02:11:05Z","timestamp":1670292665000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-020-20183-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,22]]},"references-count":71,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["20183"],"URL":"https:\/\/doi.org\/10.1038\/s41467-020-20183-3","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,22]]},"assertion":[{"value":"8 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"L.E.C. and L.W. are co-founders and shareholders in Bright Angel Therapeutics, a platform company for development of novel antifungal therapeutics. L.E.C. is a consultant for Boragen, a small-molecule development company focused on leveraging the unique chemical properties of boron chemistry for crop protection and animal health. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6429"}}