{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:04:02Z","timestamp":1790694242701,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T00:00:00Z","timestamp":1608768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI073289"],"award-info":[{"award-number":["R01 AI073289"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Candida albicans forms extremely drug-resistant biofilms, which present a serious threat to public health globally. Biofilm-based infections are difficult to treat due to the lack of efficient antifungal therapeutics, resulting in an urgent demand for the development of novel antibiofilm strategies. In this study, the antibiofilm activity of DiMIQ (5,11-dimethyl-5H-indolo[2,3-b]quinoline) was evaluated against C. albicans biofilms. DiMIQ is a synthetic derivative of indoquinoline alkaloid neocryptolepine isolated from a medicinal African plant, Cryptolepis sanguinolenta. Antifungal activity of DiMIQ was determined using the XTT assay, followed by cell wall and extracellular matrix profiling and cellular proteomes. Here, we demonstrated that DiMIQ inhibited C. albicans biofilm formation and altered fungal cell walls and the extracellular matrix. Cellular proteomics revealed inhibitory action against numerous translation-involved ribosomal proteins, enzymes involved in general energy producing processes and select amino acid metabolic pathways including alanine, aspartate, glutamate, valine, leucine and isoleucine. DiMIQ also stimulated pathways of cellular oxidation, metabolism of carbohydrates, amino acids (glycine, serine, threonine, arginine, phenylalanine, tyrosine, tryptophan) and nucleic acids (aminoacyl-tRNA biosynthesis, RNA transport, nucleotide metabolism). Our findings suggest that DiMIQ inhibits C. albicans biofilms by arresting translation and multidirectional pathway reshaping of cellular metabolism. Overall, this agent may provide a potent alternative to treating biofilm-associated Candida infections.<\/jats:p>","DOI":"10.3390\/ijms22010108","type":"journal-article","created":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T09:02:44Z","timestamp":1608800564000},"page":"108","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Label-Free Cellular Proteomics Approach to Decipher the Antifungal Action of DiMIQ, a Potent Indolo[2,3-b]Quinoline Agent, against Candida albicans Biofilms"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6343-1500","authenticated-orcid":false,"given":"Robert","family":"Zarnowski","sequence":"first","affiliation":[{"name":"Department of Medicine, School of Medicine &amp; Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"},{"name":"Department of Medical Microbiology, School of Medicine &amp; Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7921-8007","authenticated-orcid":false,"given":"Anna","family":"Jaromin","sequence":"additional","affiliation":[{"name":"Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2510-7237","authenticated-orcid":false,"given":"Agnieszka","family":"Zag\u00f3rska","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Jagiellonian University Medical College, 30-688 Cracow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddie G.","family":"Dominguez","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine &amp; Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"},{"name":"Department of Medical Microbiology, School of Medicine &amp; Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1581-0693","authenticated-orcid":false,"given":"Katarzyna","family":"Sidoryk","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Cosmetic Chemicals and Biotechnology, Team of Chemistry, \u0141ukasiewicz Research Network-Industrial Chemistry Institute, 01-793 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerzy","family":"Gubernator","sequence":"additional","affiliation":[{"name":"Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Andes","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine &amp; Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"},{"name":"Department of Medical Microbiology, School of Medicine &amp; Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1128\/CMR.00029-06","article-title":"Epidemiology of invasive candidiasis: A persistent public health problem","volume":"20","author":"Pfaller","year":"2007","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s11894-015-0436-2","article-title":"Small intestinal fungal overgrowth","volume":"17","author":"Erdogan","year":"2015","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E281","DOI":"10.1111\/1469-0691.12155","article-title":"Candidaemia in internal medicine departments: The burden of a rising problem","volume":"19","author":"Bassetti","year":"2013","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/cid\/civ933","article-title":"Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America","volume":"62","author":"Pappas","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1093\/clinids\/20.6.1531","article-title":"Nosocomial candidemia: Risk factors and attributable mortality","volume":"20","author":"Wenzel","year":"1995","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3389\/fmed.2018.00028","article-title":"Candida Biofilms: Threats, Challenges, and Promising Strategies","volume":"5","author":"Cavalheiro","year":"2018","journal-title":"Front. Med. (Lausanne)"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e01333-14","DOI":"10.1128\/mBio.01333-14","article-title":"Novel entries in a fungal biofilm matrix encyclopedia","volume":"5","author":"Zarnowski","year":"2014","journal-title":"mBio"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zarnowski, R., Sanchez, H., Covelli, A.S., Dominguez, E., Jaromin, A., Bernhardt, J., Mitchell, K.F., Heiss, C., Azadi, P., and Mitchell, A. (2018). Candida albicans biofilm-induced vesicles confer drug resistance through matrix biogenesis. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2006872"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"340","DOI":"10.3109\/10408410903241436","article-title":"Our Current Understanding of Fungal Biofilms","volume":"35","author":"Ramage","year":"2009","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1093\/cid\/cis697","article-title":"Changes in incidence and antifungal drug resistance in candidemia: Results from population-based laboratory surveillance in Atlanta and Baltimore, 2008\u20132011","volume":"55","author":"Cleveland","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"315","DOI":"10.4161\/trns.22281","article-title":"A sticky situation: Untangling the transcriptional network controlling biofilm development in Candida albicans","volume":"3","author":"Fox","year":"2012","journal-title":"Transcription"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1146\/annurev-micro-091014-104330","article-title":"Candida albicans Biofilms and Human Disease","volume":"69","author":"Nobile","year":"2015","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"742","DOI":"10.3389\/fchem.2019.00742","article-title":"Small Molecule Anti-biofilm Agents Developed on the Basis of Mechanistic Understanding of Biofilm Formation","volume":"7","author":"Qvortrup","year":"2019","journal-title":"Front. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.tim.2020.03.014","article-title":"Fatty Acids as Antibiofilm and Antivirulence Agents","volume":"28","author":"Kumar","year":"2020","journal-title":"Trends Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1462-2920.2012.02810.x","article-title":"Antibiofilm polysaccharides","volume":"15","author":"Rendueles","year":"2013","journal-title":"Environ. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3647","DOI":"10.1128\/AAC.00400-16","article-title":"Enzymes Enhance Biofilm Removal Efficiency of Cleaners","volume":"60","author":"Stiefel","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"647","DOI":"10.4155\/fmc.15.7","article-title":"Agents that inhibit bacterial biofilm formation","volume":"7","author":"Rabin","year":"2015","journal-title":"Future Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.2174\/1568026615666150427113937","article-title":"Neocryptolepine: A Promising Indoloisoquinoline Alkaloid with Interesting Biological Activity. Evaluation of the Drug and its Most Relevant Analogs","volume":"15","author":"Larghi","year":"2015","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0305-1978(02)00075-3","article-title":"Chemotaxonomic analysis of the genus Cryptolepis","volume":"31","author":"Paulo","year":"2003","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1016\/S0968-0896(99)00200-X","article-title":"Synthesis, and cytotoxic activity of some novel indolo[2,3-b]quinoline derivatives: DNA topoisomerase II inhibitors","volume":"7","author":"Kaczmarek","year":"1999","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ejmech.2014.03.060","article-title":"Searching for new derivatives of neocryptolepine: Synthesis, antiproliferative, antimicrobial and antifungal activities","volume":"78","author":"Sidoryk","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.ejmech.2015.10.022","article-title":"The synthesis of indolo[2,3-b]quinoline derivatives with a guanidine group: Highly selective cytotoxic agents","volume":"105","author":"Sidoryk","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6103","DOI":"10.1016\/j.bmcl.2012.08.032","article-title":"New derivatives of 11-methyl-6-[2-(dimethylamino)ethyl]-6H-indolo[2,3-b]quinoline as cytotoxic DNA topoisomerase II inhibitors","volume":"22","author":"Luniewski","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1248\/bpb.b110671","article-title":"Membrane Perturbations Induced by New Analogs of Neocryptolepine","volume":"35","author":"Jaromin","year":"2012","journal-title":"Biol. Pharm. Bull."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1016\/0006-2952(92)90341-F","article-title":"A carboline derivative as a novel mammalian DNA topoisomerase II targeting agent","volume":"44","author":"Pognan","year":"1992","journal-title":"Biochem. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1021\/jm00047a008","article-title":"Synthesis and structure-activity relationship of methyl-substituted indolo[2,3-b]quinolines: Novel cytotoxic, DNA topoisomerase II inhibitors","volume":"37","author":"Pognan","year":"1994","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1002\/pro.3711","article-title":"KEGG Mapper for inferring cellular functions from protein sequences","volume":"29","author":"Kanehisa","year":"2020","journal-title":"Protein Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D457","DOI":"10.1093\/nar\/gkv1070","article-title":"KEGG as a reference resource for gene and protein annotation","volume":"44","author":"Kanehisa","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_29","unstructured":"UniProt, C. (2020). UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res., gkaa1100."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.284.5418.1318","article-title":"Bacterial biofilms: A common cause of persistent infections","volume":"284","author":"Costerton","year":"1999","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrmicro2415","article-title":"The biofilm matrix","volume":"8","author":"Flemming","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/5584_2019_400","article-title":"Novel Therapies for Biofilm-Based Candida spp. Infections","volume":"1214","author":"Cernakova","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Nett, J.E., and Andes, D.R. (2020). Contributions of the Biofilm Matrix to Candida Pathogenesis. J. Fungi, 6.","DOI":"10.3390\/jof6010021"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"95","DOI":"10.17219\/dmp\/112861","article-title":"Current perspectives and the future of Candida albicans-associated denture stomatitis treatment","volume":"57","author":"Gad","year":"2020","journal-title":"Dent. Med. Probl."},{"key":"ref_35","first-page":"590","article-title":"Antimicrobial Peptides as Anti-biofilm Agents in Medical Implants","volume":"17","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5077","DOI":"10.1021\/jm300468t","article-title":"Synthesis and Biological Evaluation of New Amino Acid and Dipeptide Derivatives of Neocryptolepine as Anticancer Agents","volume":"55","author":"Sidoryk","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1128\/AAC.01056-06","article-title":"Putative role of beta-1,3 glucans in Candida albicans biofilm resistance","volume":"51","author":"Nett","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3389\/fchem.2019.00381","article-title":"Discovery of Potential Anti-infective Therapy Targeting Glutamine Synthetase in Staphylococcus xylosus","volume":"7","author":"Cui","year":"2019","journal-title":"Front. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nature14660","article-title":"Metabolic co-dependence gives rise to collective oscillations within biofilms","volume":"523","author":"Liu","year":"2015","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.tem.2017.05.007","article-title":"From Prokaryotes to Cancer: Glutamine Flux in Multicellular Units","volume":"28","author":"Erez","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.drup.2018.03.002","article-title":"Fighting bacterial persistence: Current and emerging anti-persister strategies and therapeutics","volume":"38","author":"Defraine","year":"2018","journal-title":"Drug Resist. Updat."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1080\/15476286.2018.1429879","article-title":"Drugging tRNA aminoacylation","volume":"15","author":"Ho","year":"2018","journal-title":"RNA Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/ardp.19883210807","article-title":"Cancerostatics, VI. Synthesis and antineoplastic properties of some benzo-iso-alpha-carbolines","volume":"321","author":"Kaczmarek","year":"1988","journal-title":"Arch. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/ng.605","article-title":"Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity","volume":"42","author":"Noble","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1038\/nprot.2016.132","article-title":"Large-scale production and isolation of Candida biofilm extracellular matrix","volume":"11","author":"Zarnowski","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1128\/JCM.02273-10","article-title":"Optimizing a Candida biofilm microtiter plate model for measurement of antifungal susceptibility by tetrazolium salt assay","volume":"49","author":"Nett","year":"2011","journal-title":"J. Clin. Microbiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/S0021-9673(00)80246-0","article-title":"Gas-Chromatography of Alditol Acetates on a High-Polarity Bonded-Phase Vitreous-Silica Column","volume":"249","author":"Blakeney","year":"1982","journal-title":"J. Chromatogr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4266","DOI":"10.1021\/ac000497v","article-title":"Subfemtomole MS and MS\/MS peptide sequence analysis using nano-HPLC micro-ESI Fourier transform ion cyclotron resonance mass spectrometry","volume":"72","author":"Martin","year":"2000","journal-title":"Anal. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3551","DOI":"10.1002\/(SICI)1522-2683(19991201)20:18<3551::AID-ELPS3551>3.0.CO;2-2","article-title":"Probability-based protein identification by searching sequence databases using mass spectrometry data","volume":"20","author":"Perkins","year":"1999","journal-title":"Electrophoresis"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1089\/153623102760092805","article-title":"Experimental protein mixture for validating tandem mass spectral analysis","volume":"6","author":"Keller","year":"2002","journal-title":"OMICS"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"103613","DOI":"10.1016\/j.jprot.2019.103613","article-title":"UniprotR: Retrieving and visualizing protein sequence and functional information from Universal Protein Resource (UniProt knowledgebase)","volume":"213","author":"Soudy","year":"2020","journal-title":"J. Proteom."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Bernhardt, J., Funke, S., Hecker, M., and Siebourg, J. (2009, January 23\u201326). Visualizing Gene Expression Data via Voronoi Treemaps. Proceedings of the 6th International Symposium on Voronoi Diagrams (ISVD 2009), Copenhagen, Denmark.","DOI":"10.1109\/ISVD.2009.33"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/108\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:45:46Z","timestamp":1760179546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,24]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22010108"],"URL":"https:\/\/doi.org\/10.3390\/ijms22010108","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,24]]}}}