{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:14:34Z","timestamp":1790486074871,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T00:00:00Z","timestamp":1621900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant Enterococcus faecium and Enterococcus faecalis are of considerable concern with a limited number of efficacious therapeutics available. From an initial screening of 20 peptidomimetics, 11 stable peptide\/\u03b2-peptoid hybrids were found to have antibacterial activity against eight E. faecium and E. faecalis isolates. Microbiological characterization comprised determination of minimal inhibitory concentrations (MICs), probing of synergy with antibiotics in a checkerboard assay, time\u2013kill studies, as well as assessment of membrane integrity. E. faecium isolates proved more susceptible than E. faecalis isolates, and no differences in susceptibility between the vancomycin-resistant (VRE) and -susceptible E. faecium isolates were observed. A test of three peptidomimetics (Ac-[hArg-\u03b2Nsce]6-NH2, Ac-[hArg-\u03b2Nsce-Lys-\u03b2Nspe]3-NH2 and Oct-[Lys-\u03b2Nspe]6-NH2) in combination with conventional antibiotics (vancomycin, gentamicin, ciprofloxacin, linezolid, rifampicin or azithromycin) revealed no synergy. The same three potent analogues were found to have a bactericidal effect with a membrane-disruptive mode of action. Peptidomimetics Ac-[hArg-\u03b2Nsce-Lys-\u03b2Nspe]3-NH2 and Oct-[Lys-\u03b2Nspe]6-NH2 with low MIC values (in the ranges 2\u20138 \u00b5g\/mL and 4\u201316 \u00b5g\/mL against E. faecium and E. faecalis, respectively) and displaying weak cytotoxic properties (i.e., &lt;10% hemolysis at a ~100-fold higher concentration than their MICs; IC50 values of 73 and 41 \u00b5g\/mL, respectively, against HepG2 cells) were identified as promising starting points for further optimization studies.<\/jats:p>","DOI":"10.3390\/ijms22115617","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T22:02:23Z","timestamp":1621980143000},"page":"5617","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Peptide\/\u03b2-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3840-3193","authenticated-orcid":false,"given":"Martin","family":"Vestergaard","sequence":"first","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Stigb\u00f8jlen 4, DK-1870 Frederiksberg C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bolette","family":"Skive","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Stigb\u00f8jlen 4, DK-1870 Frederiksberg C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilona","family":"Domraceva","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, 1006 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanne","family":"Ingmer","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Stigb\u00f8jlen 4, DK-1870 Frederiksberg C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2822-1927","authenticated-orcid":false,"given":"Henrik","family":"Franzyk","sequence":"additional","affiliation":[{"name":"Center for Peptide-Based Antibiotics, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1016\/j.ijantimicag.2013.04.007","article-title":"Antimicrobial resistance: Action to combat the rising microbial challenges","volume":"42","author":"Paphitou","year":"2013","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/nrd3975","article-title":"Platforms for antibiotic discovery","volume":"12","author":"Lewis","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1473-3099(17)30753-3","article-title":"Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","unstructured":"Centers for Disease Control (2019). Antibiotic Resistance Threats in the United States. Centers for Disease Control and Prevention."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e00058-18","DOI":"10.1128\/CMR.00058-18","article-title":"The Enterococcus: A model of adaptability to its environment","volume":"32","author":"Rice","year":"2019","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fiore, E., Van Tyne, D., and Gilmore, M.S. (2019). Pathogenicity of Enterococci. Gram-Positive Pathog., 378\u2013397.","DOI":"10.1128\/9781683670131.ch24"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1017\/ice.2016.174","article-title":"Antimicrobial-resistant pathogens associated with healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011\u20132014","volume":"37","author":"Weiner","year":"2016","journal-title":"Infect. Control. Hosp. Epidemiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1586\/14787210.2014.956092","article-title":"Mechanisms of antibiotic resistance in enterococci","volume":"12","author":"Miller","year":"2014","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/j.1469-0691.2010.03214.x","article-title":"Management of multidrug-resistant enterococcal infections","volume":"16","author":"Arias","year":"2010","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S1473-3099(18)30605-4","article-title":"Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: A population-level modelling analysis","volume":"19","author":"Cassini","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1080\/22221751.2020.1769500","article-title":"The ongoing challenge of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis in Europe: An epidemiological analysis of bloodstream infections","volume":"9","author":"Ayobami","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e216","DOI":"10.1016\/S1473-3099(20)30327-3","article-title":"The value of antimicrobial peptides in the age of resistance","volume":"20","author":"Magana","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.drudis.2009.10.009","article-title":"Synthetic therapeutic peptides: Science and market","volume":"15","author":"Vlieghe","year":"2010","journal-title":"Drug Discov. Today"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Molchanova, N., Hansen, P.R., and Franzyk, H. (2017). Advances in development of antimicrobial peptidomimetics as potential drugs. Molecules, 22.","DOI":"10.3390\/molecules22091430"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1073\/pnas.0708254105","article-title":"Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides","volume":"105","author":"Chongsiriwatana","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/j.bmcl.2005.11.075","article-title":"Antimicrobial \u03b2-peptoids by a block synthesis approach","volume":"16","author":"Shuey","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7553","DOI":"10.1021\/ja0107475","article-title":"De novo design, synthesis, and characterization of antimicrobial \u03b2-peptides","volume":"123","author":"Liu","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1021\/ja0666553","article-title":"Interplay among folding, sequence, and lipophilicity in the antibacterial and hemolytic activities of \u03b1\/\u03b2-peptides","volume":"129","author":"Schmitt","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1039\/c3ob40444g","article-title":"AApeptides as a new class of antimicrobial agents","volume":"11","author":"Niu","year":"2013","journal-title":"Org. Biomol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1002\/cbic.201000232","article-title":"Antimicrobial, hemolytic, and cytotoxic activities of \u03b2-peptoid\u2013peptide hybrid oligomers: Improved properties compared to natural AMPs","volume":"11","author":"Olsen","year":"2010","journal-title":"ChemBioChem"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7253","DOI":"10.1021\/jm300820a","article-title":"Antimicrobial activity of peptidomimetics against multidrug-resistant Escherichia coli: A comparative study of different backbones","volume":"55","author":"Jahnsen","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Frederiksen, N., Hansen, P.R., Bj\u00f6rkling, F., and Franzyk, H. (2019). Peptide\/peptoid hybrid oligomers: The influence of hydrophobicity and relative side-chain length on antibacterial activity and cell selectivity. Molecules, 24.","DOI":"10.3390\/molecules24244429"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hein-Kristensen, L., Knapp, K.M., Franzyk, H., and Gram, L. (2011). Bacterial membrane activity of \u03b1-peptide\/\u03b2-peptoid chimeras: Influence of amino acid composition and chain length on the activity against different bacterial strains. BMC Microbiol., 11.","DOI":"10.1186\/1471-2180-11-144"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ijantimicag.2012.09.014","article-title":"High in vitro antimicrobial activity of \u03b2-peptoid\u2013peptide hybrid oligomers against planktonic and biofilm cultures of Staphylococcus epidermidis","volume":"41","author":"Liu","year":"2013","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.resmic.2015.10.002","article-title":"Improved in vitro evaluation of novel antimicrobials: Potential synergy between human plasma and antibacterial peptidomimetics, AMPs and antibiotics against human pathogenic bacteria","volume":"167","author":"Citterio","year":"2016","journal-title":"Res. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1086\/533452","article-title":"Federal funding for the study of antimicrobial resistance in nosocomial pathogens: No ESKAPE","volume":"197","author":"Rice","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ejpb.2015.01.013","article-title":"End group modification: Efficient tool for improving activity of antimicrobial peptide analogues towards Gram-positive bacteria","volume":"95","author":"Jahnsen","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1002\/cmdc.201600553","article-title":"Lysine-based \u03b1-peptide\/\u03b2-peptoid peptidomimetics: Influence of hydrophobicity, fluorination, and distribution of cationic charge on antimicrobial activity and cytotoxicity","volume":"12","author":"Molchanova","year":"2017","journal-title":"ChemMedChem"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1021\/jm501341h","article-title":"Lipidated \u03b1-Peptide\/\u03b2-peptoid hybrids with potent anti-inflammatory activity","volume":"58","author":"Skovbakke","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19888","DOI":"10.1074\/jbc.M116.736850","article-title":"The lipidated peptidomimetic Lau-((S)-Aoc)-(Lys-\u03b2Nphe)6-NH2 is a novel formyl peptide receptor 2 agonist that activates both human and mouse neutrophil NADPH oxidase","volume":"291","author":"Holdfeldt","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1039\/C6TB00155F","article-title":"Amino acid side chains affect the bioactivity of designed short peptide amphiphiles","volume":"4","author":"Chen","year":"2016","journal-title":"J. Mater. Chem. B"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1002\/cmdc.202000526","article-title":"Alternating cationic-hydrophobic peptide\/peptoid hybrids: Influence of hydrophobicity on antibacterial activity and cell selectivity","volume":"15","author":"Frederiksen","year":"2020","journal-title":"ChemMedChem"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1016\/j.carres.2011.09.026","article-title":"Chemical structure of wall teichoic acid isolated from Enterococcus faecium strain U0317","volume":"346","author":"Bychowska","year":"2011","journal-title":"Carbohydr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.carres.2012.03.031","article-title":"The structure of the wall teichoic acid isolated from Enterococcus faecalis strain 12030","volume":"354","author":"Theilacker","year":"2012","journal-title":"Carbohydr. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"236","DOI":"10.3389\/fcimb.2019.00236","article-title":"Repurposing azithromycin and rifampicin against Gram-negative pathogens by combination with peptidomimetics","volume":"9","author":"Baker","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s15010-018-1202-9","article-title":"Vancomycin-resistant enterococci (VRE): A reason to isolate?","volume":"47","author":"Vehreschild","year":"2019","journal-title":"Infection"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1086\/313949","article-title":"Aminoglycoside resistance in enterococci","volume":"31","author":"Chow","year":"2000","journal-title":"Clin. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1016\/j.chembiol.2013.09.007","article-title":"Characterization of a proteolytically stable multifunctional host defense peptidomimetic","volume":"20","author":"Jahnsen","year":"2013","journal-title":"Chem. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Stiefel, P., Schmidt-Emrich, S., Maniura-Weber, K., and Ren, Q. (2015). Critical aspects of using bacterial cell viability assays with the fluorophores SYTO9 and propidium iodide. BMC Microbiol., 15.","DOI":"10.1186\/s12866-015-0376-x"},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.3389\/fmicb.2020.01007","article-title":"Nisin damages the septal membrane and triggers DNA condensation in methicillin-resistant Staphylococcus aureus","volume":"11","author":"Jensen","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1099\/00221287-131-8-1933","article-title":"One or two low affinity penicillin-binding proteins may be responsible for the range of susceptibility of Enterococcus faecium to benzylpenicillin","volume":"131","author":"Williamson","year":"1985","journal-title":"Microbiology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5617\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:07:50Z","timestamp":1760162870000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5617"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,25]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115617"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115617","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,25]]}}}