{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T09:08:26Z","timestamp":1778317706370,"version":"3.51.4"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,25]],"date-time":"2022-12-25T00:00:00Z","timestamp":1671926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Portuguese funds through FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia\/Minist\u00e9rio da Ci\u00eancia, Tecnologia e Ensino Superior","doi-asserted-by":"publisher","award":["POCI-01\u20130145-FEDER-007274"],"award-info":[{"award-number":["POCI-01\u20130145-FEDER-007274"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Portuguese funds through FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia\/Minist\u00e9rio da Ci\u00eancia, Tecnologia e Ensino Superior","doi-asserted-by":"publisher","award":["PTDC\/QUI-QFI\/29914\/2017"],"award-info":[{"award-number":["PTDC\/QUI-QFI\/29914\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Over recent decades, multidrug-resistant pathogens have become a global concern, with WHO even considering it one of the biggest threats to global health, food security, and development today, which led to the search for alternative antibacterial agents. A special class is formed by peptides composed by the diphenylalanine motif whose antibacterial properties result from their supramolecular arrangement into nanotubes. However, several other dipeptides that also form nanotubes have been largely overlooked. Here, we present the antibacterial activity of four dipeptide nanotubes. The results point to diverse mechanisms through which dipeptide nanotubes exert their effect against bacteria. Antibacterial activity was similar for dipeptide nanotubes sufficiently wide to allow water flux while dipeptides displaying smaller channels were inactive. This suggests that two of the tested dipeptides, L-Phe-L-Phe (FF, diphenylalanine) and L-Leu-L-Ser (LS), are pore forming structures able to induce membrane permeation and affect cellular hydration and integrity. Of these two dipeptides, only FF demonstrated potential to inhibit biofilm formation. The amyloid-like nature and hydrophobicity of diphenylalanine assemblies are probably responsible for their adhesion to cell surfaces preventing biofilm formation and bacteria attachment.<\/jats:p>","DOI":"10.3390\/ijms24010328","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T04:40:39Z","timestamp":1672116039000},"page":"328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antibacterial and Antibiofilm Properties of Self-Assembled Dipeptide Nanotubes"],"prefix":"10.3390","volume":"24","author":[{"given":"Iris","family":"Soares","sequence":"first","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1248-3452","authenticated-orcid":false,"given":"In\u00eas","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"CIIMAR\u2014Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6115-8811","authenticated-orcid":false,"given":"Paulo Martins","family":"da Costa","sequence":"additional","affiliation":[{"name":"CIIMAR\u2014Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8352-6539","authenticated-orcid":false,"given":"Lu\u00eds","family":"Gales","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"},{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1007\/s13197-016-2318-5","article-title":"Antimicrobial peptides as natural bio-preservative to enhance the shelf-life of food","volume":"53","author":"Rai","year":"2016","journal-title":"J. Food Sci. Technol."},{"key":"ref_2","first-page":"138","article-title":"Review of antimicrobial food packaging","volume":"40","author":"Ye","year":"2009","journal-title":"Nongye Jixie Xuebao\/Trans. Chin. Soc. Agric. Mach."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3109\/07388551.2011.594423","article-title":"Antimicrobial peptides: Key components of the innate immune system","volume":"32","author":"Pasupuleti","year":"2012","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"180","DOI":"10.3109\/1040841X.2012.699025","article-title":"Bacterial resistance to cationic antimicrobial peptides","volume":"39","year":"2013","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_5","first-page":"251","article-title":"Bacterial evasion of antimicrobial peptides by biofilm formation","volume":"306","author":"Otto","year":"2006","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/s41467-017-01447-x","article-title":"Self-assembling dipeptide antibacterial nanostructures with membrane disrupting activity","volume":"8","author":"Schnaider","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lombardi, L., Falanga, A., Del Genio, V., and Galdiero, S. (2019). A new hope: Self-assembling peptides with antimicrobial activity. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11040166"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.2174\/1385272819666150608220036","article-title":"Peptide self-assembly for therapeutic applications","volume":"19","author":"Gales","year":"2015","journal-title":"Curr. Org. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1016\/j.ijbiomac.2020.08.023","article-title":"Dissection of the key steps of amyloid-\u03b2 peptide 1\u201340 fibrillogenesis","volume":"164","author":"Leite","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.jssc.2017.04.035","article-title":"J-aggregation in porphyrin nanoparticles induced by diphenylalanine","volume":"252","author":"Li","year":"2017","journal-title":"J. Solid State Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1021\/jp2115719","article-title":"Reorganization of Self-Assembled Dipeptide Porphyrin J-Aggregates in Water\u2013Ethanol Mixtures","volume":"116","author":"Teixeira","year":"2012","journal-title":"J. Phys. Chem. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"19903","DOI":"10.1021\/acs.jpcc.9b03341","article-title":"Self-Assembly for Two Types of J-Aggregates: Cis-Isomers of Dye on the Carbon Nanotube Surface and Free Aggregates of Dye trans-Isomers","volume":"123","author":"Lutsyk","year":"2019","journal-title":"J. Phys. Chem. C"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20378","DOI":"10.1021\/acs.jpcc.6b06272","article-title":"Emergence of Additional Visible-Range Photoluminescence Due to Aggregation of Cyanine Dye: Astraphloxin on Carbon Nanotubes Dispersed with Anionic Surfactant","volume":"120","author":"Lutsyk","year":"2016","journal-title":"J. Phys. Chem. C"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1039\/C1JM13568F","article-title":"Peptide-based solids: Porosity and zeolitic behavior","volume":"22","author":"Afonso","year":"2012","journal-title":"J. Mater. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4777","DOI":"10.1021\/cg500925x","article-title":"Toward the construction of 3D dipeptide-metal frameworks","volume":"14","author":"Emami","year":"2014","journal-title":"Cryst. Growth Des."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7287","DOI":"10.1039\/c1cc11202c","article-title":"Metal-biomolecule frameworks (MBioFs)","volume":"47","author":"Imaz","year":"2011","journal-title":"Chem. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1126\/science.1190672","article-title":"An adaptable peptide-based porous material","volume":"329","author":"Rabone","year":"2010","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5153","DOI":"10.1002\/1521-3765(20011203)7:23<5153::AID-CHEM5153>3.0.CO;2-N","article-title":"Nanotube formation by hydrophobic dipeptides","volume":"7","year":"2001","journal-title":"Chem.\u2014Eur. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19386","DOI":"10.1039\/C4CP02085E","article-title":"Hydrophobic dipeptide crystals: A promising Ag-free class of ultramicroporous materials showing argon\/oxygen adsorption selectivity","volume":"16","author":"Afonso","year":"2014","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.1002\/anie.201000007","article-title":"Dipeptide crystals as excellent permselective materials: Sequential exclusion of argon, nitrogen, and oxygen","volume":"49","author":"Afonso","year":"2010","journal-title":"Angew. Chem.\u2014Int. Ed."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5517","DOI":"10.1002\/slct.201800559","article-title":"Transport Properties of Light Gases in Nanochannels of L\u2013Leu-L-Ser Dipeptide Crystals: A Comparative Study by Molecular Dynamics Simulations","volume":"3","author":"Biernacki","year":"2018","journal-title":"ChemistrySelect"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1039\/B820200A","article-title":"Methane, carbon dioxide and hydrogen storage in nanoporous dipeptide-based materials","volume":"3","author":"Comotti","year":"2009","journal-title":"Chem. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1039\/C2CE26392K","article-title":"Guest diffusion in dipeptide crystals","volume":"15","author":"Gales","year":"2013","journal-title":"CrystEngComm"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"112284","DOI":"10.1016\/j.micromeso.2022.112284","article-title":"Selective adsorption and separation of light hydrocarbon gases in VI\/IV dipeptide crystals","volume":"345","author":"Biernacki","year":"2022","journal-title":"Microporous Mesoporous Mater."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Dur\u00e3o, J., Vale, N., Gomes, S., Gomes, P., Barrias, C.C., and Gales, L. (2019). Nitric oxide release from antimicrobial peptide hydrogels for wound healing. Biomolecules, 9.","DOI":"10.3390\/biom9010004"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1039\/C7CC06534E","article-title":"Porous dipeptide crystals as volatile-drug vessels","volume":"54","author":"Bracco","year":"2017","journal-title":"Chem. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1039\/b915765b","article-title":"Self-assembly and application of diphenylalanine-based nanostructures","volume":"39","author":"Yan","year":"2010","journal-title":"Chem. Soc. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19775","DOI":"10.3390\/molecules201119658","article-title":"The Phe-Phe Motif for Peptide Self-Assembly in Nanomedicine","volume":"20","author":"Marchesan","year":"2015","journal-title":"Molecules"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1039\/B305984G","article-title":"Nanotubes from hydrophobic dipeptides: Pore size regulation through side chain substitution","volume":"27","year":"2003","journal-title":"New J. Chem."},{"key":"ref_31","first-page":"4288","article-title":"Microporous organic crystals: An unusual case for L-leucyl-L-serine","volume":"34","author":"Nilsen","year":"2005","journal-title":"Chem. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1002\/chem.200601427","article-title":"Microporous organic materials from hydrophobic dipeptides","volume":"13","year":"2007","journal-title":"Chem.\u2014Eur. J."},{"key":"ref_33","first-page":"2332","article-title":"The structure of nanotubes formed by diphenylalanine, the core recognition motif of Alzheimer\u2019s \u03b2-amyloid polypeptide","volume":"22","year":"2006","journal-title":"Chem. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1021\/nn404237f","article-title":"Expanding the solvent chemical space for self-assembly of dipeptide nanostructures","volume":"8","author":"Mason","year":"2014","journal-title":"ACS Nano"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s40121-019-00260-x","article-title":"Infectious Disease Management and Control with Povidone Iodine","volume":"8","author":"Eggers","year":"2019","journal-title":"Infect. Dis. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1086\/381972","article-title":"Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections","volume":"38","author":"Pankey","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e01934-17","DOI":"10.1128\/JCM.01934-17","article-title":"CLSI methods development and standardization working group best practices for evaluation of antimicrobial susceptibility tests","volume":"56","author":"Humphries","year":"2018","journal-title":"J. Clin. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Munita, J.M., and Arias, C.A. (2016). Mechanisms of antibiotic resistance. Microbiol. Spectr., 4.","DOI":"10.1128\/microbiolspec.VMBF-0016-2015"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10205","DOI":"10.1021\/la4019162","article-title":"l-Diphenylalanine Microtubes As a Potential Drug-Delivery System: Characterization, Release Kinetics, and Cytotoxicity","volume":"29","author":"Silva","year":"2013","journal-title":"Langmuir"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.actbio.2018.07.033","article-title":"Self-assembling diphenylalanine peptide nanotubes selectively eradicate bacterial biofilm infection","volume":"77","author":"Porter","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6026","DOI":"10.1021\/acs.jpcc.7b11863","article-title":"Dipeptide Crystals as Reverse Osmosis Membranes for Water Desalination: Atomistic Simulation","volume":"122","author":"Zhao","year":"2018","journal-title":"J. Phys. Chem. C"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.2174\/092986711795656216","article-title":"Antimicrobial strategies effective against infectious bacterial biofilms","volume":"18","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_43","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_44","doi-asserted-by":"crossref","first-page":"340ra72","DOI":"10.1126\/scitranslmed.aaf1059","article-title":"Amyloid-\u03b2 peptide protects against microbial infection in mouse and worm models of Alzheimer\u2019s disease","volume":"8","author":"Kumar","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053229614024218","article-title":"Crystal structure refinement with SHELXL","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr. Sect. C Struct. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sim\u00f5es, R.R., Aires-de-Sousa, M., Concei\u00e7\u00e3o, T., Antunes, F., da Costa, P.M., and de Lencastre, H. (2011). High prevalence of EMRSA-15 in Portuguese public buses: A worrisome finding. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017630"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"426","DOI":"10.2166\/wh.2014.160","article-title":"High prevalence of multidrug-resistant Escherichia coli and Enterococcus spp. in river water, upstream and downstream of a wastewater treatment plant","volume":"12","author":"Bessa","year":"2014","journal-title":"J. Water Health"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jac\/dkg301","article-title":"Synergy, antagonism, and what the chequerboard puts between them","volume":"52","author":"Odds","year":"2003","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"18472","DOI":"10.1021\/acsomega.9b03002","article-title":"Synthesis and Spectral Properties of 8-Anilinonaphthalene-1-sulfonic Acid (ANS) Derivatives Prepared by Microwave-Assisted Copper(0)-Catalyzed Ullmann Reaction","volume":"4","author":"Wang","year":"2019","journal-title":"ACS Omega"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Kumla, D., Dethoup, T., Gales, L., Pereira, J.A., Freitas-Silva, J., Costa, P.M., Silva, A.M.S., Pinto, M.M.M., and Kijjoa, A. (2019). Erubescensoic Acid, a new polyketide and a xanthonopyrone SPF-3059-26 From the culture of the marine sponge-associated fungus penicillium erubescens KUFA 0220 and Antibacterial activity evaluation of some of its constituents. Molecules, 24.","DOI":"10.3390\/molecules24010208"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/j.1600-0463.2007.apm_630.x","article-title":"Quantification of biofilm in microtiter plates: Overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci","volume":"115","author":"Hola","year":"2007","journal-title":"APMIS"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/328\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:50:45Z","timestamp":1760147445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,25]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24010328"],"URL":"https:\/\/doi.org\/10.3390\/ijms24010328","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,25]]}}}