{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:47:50Z","timestamp":1787989670142,"version":"build-2784847793"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:00:00Z","timestamp":1671753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Singapore-MIT Alliance for Research and Technology (SMART)","award":["ING-000834 BIO IGN"],"award-info":[{"award-number":["ING-000834 BIO IGN"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Many antibiotics are ineffective in killing Gram-negative bacteria due to the permeability barrier of the outer-membrane LPS. Infections caused by multi-drug-resistant Gram-negative pathogens require new antibiotics, which are often difficult to develop. Antibiotic potentiators disrupt outer-membrane LPS and can assist the entry of large-scaffold antibiotics to the bacterial targets. In this work, we designed a backbone-cyclized ultra-short, six-amino-acid-long (WKRKRY) peptide, termed cWY6 from LPS binding motif of \u03b2-boomerang bactericidal peptides. The cWY6 peptide does not exhibit any antimicrobial activity; however, it is able to permeabilize the LPS outer membrane. Our results demonstrate the antibiotic potentiator activity in the designed cWY6 peptide for several conventional antibiotics (vancomycin, rifampicin, erythromycin, novobiocin and azithromycin). Remarkably, the short cWY6 peptide exhibits wound-healing activity in in vitro assays. NMR, computational docking and biophysical studies describe the atomic-resolution structure of the peptide in complex with LPS and mode of action in disrupting the outer membrane. The dual activities of cWY6 peptide hold high promise for further translation to therapeutics.<\/jats:p>","DOI":"10.3390\/ijms24010263","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T04:35:43Z","timestamp":1672115743000},"page":"263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Ultra-Short Cyclized \u03b2-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound Healing"],"prefix":"10.3390","volume":"24","author":[{"given":"Sheetal","family":"Sinha","sequence":"first","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore"},{"name":"Advanced Environmental Biotechnology Centre, Nanyang Environment and Water Research Institute, Nanyang Technological University, 1 Cleantech Loop, Singapore 637141, Singapore"},{"name":"Interdisciplinary Graduate School, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidhya Bharathi","family":"Dhanabal","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica Lavanya","family":"Manivannen","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3423-8474","authenticated-orcid":false,"given":"Floriana","family":"Cappiello","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suet-Mien","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7015-1937","authenticated-orcid":false,"given":"Surajit","family":"Bhattacharjya","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1126\/science.321.5887.356","article-title":"The bacteria fight back","volume":"321","author":"Taubes","year":"2008","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1126\/science.352.6287.758","article-title":"Resistance fighters","volume":"352","author":"Kupferschmidt","year":"2016","journal-title":"Science"},{"key":"ref_3","unstructured":"Savage, N. (2020). Overcoming resistance. Antimicrobial Resistance, WHO."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.mib.2017.10.028","article-title":"Global antimicrobial resistance in Gram-negative pathogens and clinical need","volume":"39","author":"Theuretzbacher","year":"2017","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/nrd4675","article-title":"Antibiotic resistance breakers: Can repurposed drugs fill the antibiotic discovery void?","volume":"14","author":"Brown","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1021\/acsinfecdis.0c00805","article-title":"Selective Permeabilization of Gram-Negative Bacterial Membranes Using Multivalent Peptide Constructs for Antibiotic Sensitization","volume":"7","author":"Chan","year":"2021","journal-title":"ACS Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1021\/acsinfecdis.5b00097","article-title":"Permeability Barrier of Gram-Negative Cell Envelopes and Approaches to Bypass It","volume":"1","author":"Zgurskaya","year":"2015","journal-title":"ACS Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1128\/MMBR.67.4.593-656.2003","article-title":"Molecular basis of bacterial outer membrane permeability revisited","volume":"67","author":"Nikaido","year":"2003","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bhattacharjya, S., and Straus, S.K. (2020). Design, Engineering and Discovery of Novel \u03b1-Helical and \u03b2-Boomerang Antimicrobial Peptides against Drug Resistant Bacteria. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165773"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/s41586-019-1665-6","article-title":"Chimeric peptidomimetic antibiotics against Gram-negative bacteria","volume":"576","author":"Luther","year":"2019","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100078","DOI":"10.1016\/j.medidd.2020.100078","article-title":"Emerging peptide antibiotics with therapeutic potential","volume":"9","author":"Upert","year":"2021","journal-title":"Med. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis","volume":"399","author":"Murray","year":"2022","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Barreto-Santamar\u00eda, A., Ar\u00e9valo-Pinz\u00f3n, G., Patarroyo, M.A., and Patarroyo, M.E. (2021). How to Combat Gram-Negative Bacteria Using Antimicrobial Peptides: A Challenge or an Unattainable Goal?. Antibiotics, 10.","DOI":"10.3390\/antibiotics10121499"},{"key":"ref_14","unstructured":"O\u2019Neill, J. (2020, August 21). Tackling drug-resistant infections globally: Final report and recommendations. Available online: https:\/\/apo.org.au\/node\/63983."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Nicolas, I., Bordeau, V., Bondon, A., Baudy-Floc\u2019h, M., and Felden, B. (2019). Novel antibiotics effective against gram-positive and -negative multi-resistant bacteria with limited resistance. PLoS Biol., 17.","DOI":"10.1371\/journal.pbio.3000337"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.3389\/fmicb.2019.01689","article-title":"Polymyxins and Their Potential Next Generation as Therapeutic Antibiotics","volume":"10","author":"Vaara","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1021\/jm900999h","article-title":"Structure-activity relationships of polymyxin antibiotics","volume":"53","author":"Velkov","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/1751-7915.12044","article-title":"Antibiotic adjuvants: Identification and clinical use","volume":"6","author":"Bernal","year":"2013","journal-title":"Microb. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.tim.2016.06.009","article-title":"Antibiotic Adjuvants: Rescuing Antibiotics from Resistance","volume":"24","author":"Wright","year":"2016","journal-title":"Trends Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pletzer, D., Mansour, S.C., and Hancock, R.E.W. (2018). Synergy between conventional antibiotics and anti-biofilm peptides in a murine, sub-cutaneous abscess model caused by recalcitrant ESKAPE pathogens. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007084"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17629","DOI":"10.1038\/s41598-017-17772-6","article-title":"Increasing the permeability of Escherichia coli using MAC13243","volume":"17","author":"Muheim","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/jac\/dkx394","article-title":"Polymyxin derivatives NAB739 and NAB815 are more effective than polymyxin B in murine Escherichia coli pyelonephritis","volume":"73","author":"Vaara","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00200-17","DOI":"10.1128\/AAC.00200-17","article-title":"Potentiation of Antibiotic Activity by a Novel Cationic Peptide: Potency and Spectrum of Activity of SPR741","volume":"61","author":"Corbett","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","first-page":"251","article-title":"Polymyxin B Nonapeptide: Conformations in Water and in the Lipopolysaccharide-Bound State Determined by Two-Dimensional NMR and Molecular Dynamics","volume":"41","author":"Bhattacharjya","year":"1997","journal-title":"Biopolym. Orig. Res. Biomol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5864","DOI":"10.1021\/bi6025159","article-title":"High-resolution solution structure of a designed peptide bound to lipopolysaccharide: Transferred nuclear Overhauser effects, micelle selectivity, and anti-endotoxic activity","volume":"46","author":"Bhattacharjya","year":"2007","journal-title":"Biochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"21991","DOI":"10.1074\/jbc.M109.013573","article-title":"Designed beta-boomerang antiendotoxic and antimicrobial peptides: Structures and activities in lipopolysaccharide","volume":"284","author":"Bhunia","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3390\/ph7040482","article-title":"\u03b2-Boomerang Antimicrobial and Antiendotoxic Peptides: Lipidation and Disulfide Bond Effects on Activity and Structure","volume":"7","author":"Mohanram","year":"2014","journal-title":"Pharmaceuticals"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1128\/AAC.02321-13","article-title":"Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap","volume":"58","author":"Mohanram","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2850","DOI":"10.1016\/j.bmc.2017.08.006","article-title":"Advances in macrocyclic peptide-based antibiotics","volume":"26","author":"Luther","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.cbpa.2017.02.004","article-title":"Protein epitope mimetic macrocycles as biopharmaceuticals","volume":"38","author":"Luther","year":"2017","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.cbpa.2017.02.006","article-title":"Cyclic peptide therapeutics: Past, present and future","volume":"38","author":"Zorzi","year":"2017","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_33","first-page":"353","article-title":"Automated NMR protein structure calculation with CYANA","volume":"278","year":"2004","journal-title":"Methods Mol. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"W63","DOI":"10.1093\/nar\/gkl341","article-title":"PREDITOR: A web server for predicting protein torsion angle restraints","volume":"34","author":"Berjanskii","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"W363","DOI":"10.1093\/nar\/gki481","article-title":"PatchDock and SymmDock: Servers for rigid and symmetric docking","volume":"33","author":"Inbar","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14650","DOI":"10.1021\/acsomega.8b01876","article-title":"Cell-Selective pore forming antimicrobial peptides of the prodomain of human furin: A conserved aromatic\/cationic sequence mapping, membrane disruption, and atomic-resolution structure and dynamics","volume":"3","author":"Sinha","year":"2018","journal-title":"ACS Omega"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1080\/19336918.2016.1243645","article-title":"Expression of kindlin-3 in melanoma cells impedes cell migration and metastasis","volume":"11","author":"Feng","year":"2017","journal-title":"Cell Adhes. Migr."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Di Grazia, A., Cappiello, F., Imanishi, A., Mastrofrancesco, A., Picardo, M., Paus, R., and Mangoni, M.L. (2015). The Frog Skin-Derived Antimicrobial Peptide Esculentin-1a(1-21)NH2 Promotes the Migration of Human HaCaT Keratinocytes in an EGF Receptor-Dependent Manner: A Novel Promoter of Human Skin Wound Healing?. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0128663"},{"key":"ref_39","first-page":"56825","article-title":"A Novel In Vitro Wound Healing Assay to Evaluate Cell Migration","volume":"17","author":"Cappiello","year":"2018","journal-title":"J. Vis. Exp."},{"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."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/263\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:49:17Z","timestamp":1760147357000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,23]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24010263"],"URL":"https:\/\/doi.org\/10.3390\/ijms24010263","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,23]]}}}