{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T07:14:31Z","timestamp":1760426071278,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T00:00:00Z","timestamp":1660694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Centre for Antibiotic Resistance Research (CARe) at University of Gothenburg","award":["STINT-PROJ-20181009558P"],"award-info":[{"award-number":["STINT-PROJ-20181009558P"]}]},{"name":"Sven and Lilly Lawski Foundation","award":["STINT-PROJ-20181009558P"],"award-info":[{"award-number":["STINT-PROJ-20181009558P"]}]},{"DOI":"10.13039\/501100002322","name":"Coordination for the Improvement of Higher Education (CAPES), Brazil","doi-asserted-by":"publisher","award":["STINT-PROJ-20181009558P"],"award-info":[{"award-number":["STINT-PROJ-20181009558P"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Antibiotic resistance among bacteria is a growing global challenge. A major reason for this is the limited progress in developing new classes of antibiotics active against Gram-negative bacteria. Here, we investigate the antibacterial activity of a dicationic bisguanidine-arylfuran, originally developed as an antitrypanosomal agent, and new derivatives thereof. The compounds showed good activity (EC50 2\u201320 \u00b5M) against antibiotic-resistant isolates of the Gram-negative members of the ESKAPE group (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) and Escherichia coli with different antibiotic susceptibility patterns, including ESBL isolates. Cytotoxicity was moderate, and several of the new derivatives were less cytotoxic than the lead molecule, offering better selectivity indices (40\u201380 for several ESKAPE isolates). The molecular mechanism for the antibacterial activity of these molecules is unknown, but sensitivity profiling against human ESKAPE isolates and E. coli collections with known susceptibility patterns against established antibiotics indicates that it is distinct from lactam and quinolone antibiotics.<\/jats:p>","DOI":"10.3390\/antibiotics11081115","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T21:23:56Z","timestamp":1660771436000},"page":"1115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Development of Dicationic Bisguanidine-Arylfuran Derivatives as Potent Agents against Gram-Negative Bacteria"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3469-703X","authenticated-orcid":false,"given":"Catarina","family":"Bourgard","sequence":"first","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden"},{"name":"Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, S-405 30 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1125-2399","authenticated-orcid":false,"given":"Diego","family":"Rodr\u00edguez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8868-1204","authenticated-orcid":false,"given":"Anastasia","family":"Rudenko","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden"},{"name":"Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, S-405 30 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolin","family":"Rutgersson","sequence":"additional","affiliation":[{"name":"Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, S-405 30 Gothenburg, Sweden"},{"name":"Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, S-413 46 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6509-507X","authenticated-orcid":false,"given":"Martin","family":"Palm","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden"},{"name":"Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, S-405 30 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5496-0328","authenticated-orcid":false,"given":"D. G. Joakim","family":"Larsson","sequence":"additional","affiliation":[{"name":"Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, S-405 30 Gothenburg, Sweden"},{"name":"Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, S-413 46 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0841-4908","authenticated-orcid":false,"given":"Anne","family":"Farewell","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden"},{"name":"Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, S-405 30 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3621-4222","authenticated-orcid":false,"given":"Morten","family":"Gr\u00f8tli","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0967-8729","authenticated-orcid":false,"given":"Per","family":"Sunnerhagen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden"},{"name":"Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, S-405 30 Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"key":"ref_1","unstructured":"Antimicrobial Resistance, Collaborators (2022). Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet, 399, 629\u2013655."},{"key":"ref_2","unstructured":"WHO (2022, May 19). 2020 Antibacterial Agents in Clinical and Preclinical Development: An Overview and Analysis. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240021303."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113293","DOI":"10.1016\/j.ejmech.2021.113293","article-title":"Antimicrobial drugs bearing guanidine moieties: A review","volume":"216","author":"Kim","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1021\/acs.jmedchem.5b01912","article-title":"Antibacterial diamines targeting bacterial membranes","volume":"59","author":"Wang","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7113","DOI":"10.1021\/jm901017t","article-title":"Asymmetrical diaromatic guanidinium\/2-aminoimidazolinium derivatives: Synthesis and DNA affinity","volume":"52","author":"Nagle","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Van Voorhis, W.C., Adams, J.H., Adelfio, R., Ahyong, V., Akabas, M.H., Alano, P., Alday, A., Aleman Resto, Y., Alsibaee, A., and Alzualde, A. (2016). Open source drug discovery with the Malaria Box compound collection for neglected diseases and beyond. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005763"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e382","DOI":"10.1016\/S2666-5247(21)00326-8","article-title":"Searching for new therapeutic options for the uncommon pathogen Mycobacterium chimaera: An open drug discovery approach","volume":"3","author":"Cantillon","year":"2022","journal-title":"Lancet Microbe"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1021\/jm000413a","article-title":"Diguanidino and \u201creversed\u201d diamidino 2,5-diarylfurans as antimicrobial agents","volume":"44","author":"Stephens","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1016\/S0960-894X(03)00319-6","article-title":"The activity of diguanidino and \u2018reversed\u2019 diamidino 2,5-diarylfurans versus Trypanosoma cruzi and Leishmania donovani","volume":"13","author":"Stephens","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e00379-17","DOI":"10.1128\/AAC.00379-17","article-title":"Screening the Medicines for Malaria Venture Pathogen Box across multiple pathogens reclassifies starting points for open-source drug discovery","volume":"61","author":"Duffy","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3389\/fcimb.2018.00210","article-title":"Evaluating new compounds to treat Burkholderia pseudomallei infections","volume":"8","author":"Ross","year":"2018","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5525","DOI":"10.1016\/j.bmcl.2014.09.081","article-title":"Synthesis of linear and cyclic guazatine derivatives endowed with antibacterial activity","volume":"24","author":"Maccari","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8251","DOI":"10.1038\/s41598-017-08749-6","article-title":"Identification, synthesis and biological activity of alkyl-guanidine oligomers as potent antibacterial agents","volume":"7","author":"Zamperini","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9162","DOI":"10.1021\/acs.jmedchem.8b00619","article-title":"Alkyl-guanidine compounds as potent broad-spectrum antibacterial agents: Chemical library extension and biological characterization","volume":"61","author":"Pasero","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.ejmech.2019.05.087","article-title":"Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies","volume":"178","author":"Masci","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1080\/14756366.2019.1702654","article-title":"Synthesis, antibacterial and anticancer activity, and docking study of aminoguanidines containing an alkynyl moiety","volume":"35","author":"Deng","year":"2020","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10160","DOI":"10.1021\/jm3012728","article-title":"A bactericidal guanidinomethyl biaryl that alters the dynamics of bacterial FtsZ polymerization","volume":"55","author":"Kaul","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.cbi.2017.12.009","article-title":"Aminoguanidine hydrazones (AGH\u2019s) as modulators of norfloxacin resistance in Staphylococcus aureus that overexpress NorA efflux pump","volume":"280","author":"Dantas","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1002\/cmdc.201200150","article-title":"Selectively guanidinylated aminoglycosides as antibiotics","volume":"7","author":"Fair","year":"2012","journal-title":"ChemMedChem"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1515\/HC.1999.5.4.301","article-title":"Palladium catalyzed cross-coupling reactions for the synthesis of 2,5-disubstituted furans","volume":"5","author":"Kumar","year":"1999","journal-title":"Heterocycl. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4243","DOI":"10.1016\/j.bmcl.2005.06.077","article-title":"Design and synthesis of a novel peptidomimetic inhibitor of HIV-1 Tat-TAR interactions: Squaryldiamide as a new potential bioisostere of unsubstituted guanidine","volume":"15","author":"Lee","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1128\/jb.157.2.690-693.1984","article-title":"Standard reference strains of Escherichia coli from natural populations","volume":"157","author":"Ochman","year":"1984","journal-title":"J. Bacteriol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1099\/mic.0.000063","article-title":"Guide to the various phylogenetic classification schemes for Escherichia coli and the correspondence among schemes","volume":"161","author":"Clermont","year":"2015","journal-title":"Microbiology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1128\/AAC.44.6.1568-1574.2000","article-title":"Antibiotic resistance in the ECOR collection: Integrons and identification of a novel aad gene","volume":"44","author":"Mazel","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jgar.2020.01.024","article-title":"Recurrence of urinary tract infections with extended-spectrum beta-lactamase-producing Escherichia coli caused by homologous strains among which clone ST131-O25b is dominant","volume":"22","author":"Karami","year":"2020","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Karami, N., KK, S., Yazdanshenas, S., Lin, Y.L., Jaen-Luchoro, D., Ekedahl, E., Parameshwaran, S., Lindblom, A., \u00c5hren, C., and Westerlund, F. (2021). Identity of blaCTX-M carrying plasmids in sequential ESBL-E. coli isolates from patients with recurrent urinary tract infections. Microorganisms, 9.","DOI":"10.3390\/microorganisms9061138"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_28","first-page":"Doc05","article-title":"Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria?","volume":"12","author":"Exner","year":"2017","journal-title":"GMS Hyg. Infect. Control."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kyriakidis, I., Vasileiou, E., Pana, Z.D., and Tragiannidis, A. (2021). Acinetobacter baumannii antibiotic resistance mechanisms. Pathogens, 10.","DOI":"10.3390\/pathogens10030373"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e00309-15","DOI":"10.1128\/mBio.00309-15","article-title":"Contribution of resistance-nodulation-cell division efflux systems to antibiotic resistance and biofilm formation in Acinetobacter baumannii","volume":"6","author":"Yoon","year":"2015","journal-title":"mBio"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/femsre\/fux013","article-title":"Klebsiella pneumoniae: A major worldwide source and shuttle for antibiotic resistance","volume":"41","author":"Kondratyeva","year":"2017","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"913","DOI":"10.3389\/fmicb.2019.00913","article-title":"Tolerance and resistance of Pseudomonas aeruginosa biofilms to antimicrobial agents\u2014How P. aeruginosa can escape antibiotics","volume":"10","author":"Ciofu","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature01097","article-title":"Genome sequence of the human malaria parasite Plasmodium falciparum","volume":"419","author":"Gardner","year":"2002","journal-title":"Nature"},{"key":"ref_34","unstructured":"(2022, April 12). PubChem, Bethesda (MD): National Library of Medicine (US), N.C.f.B.I. PubChem Bioassay Record for AID 1314398, Antitrypanosoma Cruzi Activity IC50 (uM), Source: ChEMBL, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/bioassay\/1314398."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.1112631","article-title":"The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease","volume":"309","author":"Myler","year":"2005","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7163","DOI":"10.1002\/ejoc.201101102","article-title":"Methyl 2-furoate: An alternative reagent to furan for palladium-catalysed direct arylation","volume":"2011","author":"Fu","year":"2011","journal-title":"Eur. J. Organ. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1590\/S0100-40422008000200013","article-title":"S\u00edntese, avalia\u00e7\u00e3o biol\u00f3gica e modelagem molecular de arilfuranos como inibidores da enzima tripanotiona redutase","volume":"31","author":"Zani","year":"2008","journal-title":"Quim. Nova"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"330","DOI":"10.3181\/00379727-48-13311","article-title":"A protein-free medium for primary isolation of the gonococcus and meningococcus","volume":"48","author":"Mueller","year":"1941","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1128\/am.16.11.1742-1744.1968","article-title":"Limitations of thioglycolate broth as a sterility test medium for materials exposed to gaseous ethylene oxide","volume":"16","author":"Doyle","year":"1968","journal-title":"Appl. Envion. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.ymeth.2007.01.006","article-title":"Microtitre plate-based antibacterial assay incorporating resazurin as an indicator of cell growth, and its application in the in vitro antibacterial screening of phytochemicals","volume":"42","author":"Sarker","year":"2007","journal-title":"Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"djv073","DOI":"10.1093\/jnci\/djv073","article-title":"MCF-7 cells\u2014Changing the course of breast cancer research and care for 45 years","volume":"107","author":"Lee","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Arzumanian, V.A., Kiseleva, O.I., and Poverennaya, E.V. (2021). The curious case of the HepG2 cell line: 40 years of expertise. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313135"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3080","DOI":"10.1021\/acs.jnatprod.1c00811","article-title":"Oxygenated cyclohexene derivatives from the stem and root barks of Uvaria pandensis","volume":"84","author":"Maeda","year":"2021","journal-title":"J. Nat. Prod."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1534\/g3.116.032342","article-title":"Scan-o-matic: High-resolution microbial phenomics at a massive scale","volume":"6","author":"Zackrisson","year":"2016","journal-title":"G3 Genes Genomes Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e01226-20","DOI":"10.1128\/mSystems.01226-20","article-title":"A high-throughput method for screening for factors controlling bacterial conjugation of antibiotic resistance","volume":"5","author":"Alalam","year":"2020","journal-title":"Msystems"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/11\/8\/1115\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:11:20Z","timestamp":1760141480000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/11\/8\/1115"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,17]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["antibiotics11081115"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics11081115","relation":{},"ISSN":["2079-6382"],"issn-type":[{"type":"electronic","value":"2079-6382"}],"subject":[],"published":{"date-parts":[[2022,8,17]]}}}