{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:11:40Z","timestamp":1787497900013,"version":"build-2736575974"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,12,22]],"date-time":"2017-12-22T00:00:00Z","timestamp":1513900800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,12,22]],"date-time":"2017-12-22T00:00:00Z","timestamp":1513900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Antibiotics are unable to remove biofilms from surgical implants. This high antibiotic tolerance is related to bacterial persisters, a sub-population of bacteria phenotypically tolerant to antibiotics secondary to a reduced metabolic state. WLBU2 is an engineered cationic amphipathic peptide designed to maximize antimicrobial activity with minimal mammalian cell toxicity. The objective of this study was to test the ability of WLBU2 to remove\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    surgical implant biofilms. WLBU2 effectively treated\n                    <jats:italic>S. aureus<\/jats:italic>\n                    biofilms formed by a variety of clinical MSSA and MRSA strains and created culture-negative implants in the\n                    <jats:italic>in vitro<\/jats:italic>\n                    biofilm model. Blocking bacterial metabolism by inhibiting oxidative phosphorylation did not affect WLBU2 killing compared to decreased killing by cefazolin. In the surgical implant infection animal model, WLBU2 decreased biofilm mass as compared to control, untreated samples. WLBU2 could rapidly eliminate implants\n                    <jats:italic>in vitro<\/jats:italic>\n                    and had sufficient efficacy\n                    <jats:italic>in vivo<\/jats:italic>\n                    with minimal systemic toxicity.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-17780-6","type":"journal-article","created":{"date-parts":[[2017,12,18]],"date-time":"2017-12-18T10:36:54Z","timestamp":1513593414000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Elimination of Antibiotic Resistant Surgical Implant Biofilms Using an Engineered Cationic Amphipathic Peptide WLBU2"],"prefix":"10.1038","volume":"7","author":[{"given":"Jonathan B.","family":"Mandell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berthony","family":"Deslouches","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald C.","family":"Montelaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7699-5396","authenticated-orcid":false,"given":"Robert M. Q.","family":"Shanks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Doi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth L.","family":"Urish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,22]]},"reference":[{"key":"17780_CR1","unstructured":"Kane, R. L. et al. Total knee replacement. Evid Rep Technol Assess (Summ), 1\u20138 (2003)."},{"key":"17780_CR2","unstructured":"Pfuntner, A., Wier, L. M. & Stocks, C. In Healthcare Cost and Utilization Project (HCUP) Statistical Briefs (Agency for Healthcare Research and Quality (US), 2006)."},{"key":"17780_CR3","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1007\/s11999-008-0209-4","volume":"466","author":"L Pulido","year":"2008","unstructured":"Pulido, L., Ghanem, E., Joshi, A., Purtill, J. J. & Parvizi, J. Periprosthetic joint infection: the incidence, timing, and predisposing factors. Clin Orthop Relat Res \n                           466, 1710\u20131715, https:\/\/doi.org\/10.1007\/s11999-008-0209-4 (2008).","journal-title":"Clin Orthop Relat Res"},{"key":"17780_CR4","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1016\/j.arth.2007.10.017","volume":"23","author":"SM Kurtz","year":"2008","unstructured":"Kurtz, S. M. et al. Infection burden for hip and knee arthroplasty in the United States. J Arthroplasty \n                           23, 984\u2013991, https:\/\/doi.org\/10.1016\/j.arth.2007.10.017 (2008).","journal-title":"J Arthroplasty"},{"key":"17780_CR5","unstructured":"Manrique, J. G. M., Chen, A. F. & Parvizi, J. In Total Knee Arthroplasty: A Comprehensive Guide (ed Oussedik S. Rodr\u00cdguez-Merch\u00e1n E.C) Ch. 18, (Springer, 2015)."},{"key":"17780_CR6","doi-asserted-by":"publisher","first-page":"2177","DOI":"10.2106\/JBJS.L.00789","volume":"95","author":"B Zmistowski","year":"2013","unstructured":"Zmistowski, B., Karam, J. A., Durinka, J. B., Casper, D. S. & Parvizi, J. Periprosthetic joint infection increases the risk of one-year mortality. J Bone Joint Surg Am \n                           95, 2177\u20132184, https:\/\/doi.org\/10.2106\/JBJS.L.00789 (2013).","journal-title":"J Bone Joint Surg Am"},{"key":"17780_CR7","unstructured":"(Atlanta: American Cancer Society, 2012)."},{"key":"17780_CR8","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1476-0711-8-28","volume":"8","author":"RK Pettit","year":"2009","unstructured":"Pettit, R. K., Weber, C. A. & Pettit, G. R. Application of a high throughput Alamar blue biofilm susceptibility assay to Staphylococcus aureus biofilms. Ann Clin Microbiol Antimicrob \n                           8, 28, https:\/\/doi.org\/10.1186\/1476-0711-8-28 (2009).","journal-title":"Ann Clin Microbiol Antimicrob"},{"key":"17780_CR9","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.1056\/NEJMra040181","volume":"351","author":"W Zimmerli","year":"2004","unstructured":"Zimmerli, W., Trampuz, A. & Ochsner, P. E. Prosthetic-joint infections. N Engl J Med \n                           351, 1645\u20131654, https:\/\/doi.org\/10.1056\/NEJMra040181 (2004).","journal-title":"N Engl J Med"},{"key":"17780_CR10","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1128\/CMR.15.2.167-193.2002","volume":"15","author":"RM Donlan","year":"2002","unstructured":"Donlan, R. M. & Costerton, J. W. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev \n                           15, 167\u2013193 (2002).","journal-title":"Clin Microbiol Rev"},{"key":"17780_CR11","doi-asserted-by":"crossref","unstructured":"Stewart, P. S. M. P. & Ghannoum, M. A. In Microbial Biofilms (ed O\u2019Toole GA Ghannoum M) 250\u2013268 (ASM Press, 2004).","DOI":"10.1128\/9781555817718.ch14"},{"key":"17780_CR12","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1007\/s11999-016-4720-8","volume":"474","author":"KL Urish","year":"2016","unstructured":"Urish, K. L. et al. Antibiotic-tolerant Staphylococcus aureus Biofilm Persists on Arthroplasty Materials. Clin Orthop Relat Res \n                           474, 1649\u20131656, https:\/\/doi.org\/10.1007\/s11999-016-4720-8 (2016).","journal-title":"Clin Orthop Relat Res"},{"key":"17780_CR13","doi-asserted-by":"publisher","first-page":"E2528","DOI":"10.1073\/pnas.1301023110","volume":"110","author":"RA Fasani","year":"2013","unstructured":"Fasani, R. A. & Savageau, M. A. Molecular mechanisms of multiple toxin-antitoxin systems are coordinated to govern the persister phenotype. Proc Natl Acad Sci USA \n                           110, E2528\u20132537, https:\/\/doi.org\/10.1073\/pnas.1301023110. (2013).","journal-title":"Proc Natl Acad Sci USA"},{"key":"17780_CR14","doi-asserted-by":"publisher","first-page":"e1002954","DOI":"10.1371\/journal.ppat.1002954","volume":"8","author":"JP Norton","year":"2012","unstructured":"Norton, J. P. & Mulvey, M. A. Toxin-antitoxin systems are important for niche-specific colonization and stress resistance of uropathogenic Escherichia coli. PLoS Pathog \n                           8, e1002954, https:\/\/doi.org\/10.1371\/journal.ppat.1002954 (2012).","journal-title":"PLoS Pathog"},{"key":"17780_CR15","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1038\/nchembio.1062","volume":"8","author":"X Wang","year":"2012","unstructured":"Wang, X. et al. A new type V toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS. Nat Chem Biol \n                           8, 855\u2013861, https:\/\/doi.org\/10.1038\/nchembio.1062 (2012).","journal-title":"Nat Chem Biol"},{"key":"17780_CR16","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1128\/AAC.02135-12","volume":"57","author":"BW Kwan","year":"2013","unstructured":"Kwan, B. W., Valenta, J. A., Benedik, M. J. & Wood, T. K. Arrested protein synthesis increases persister-like cell formation. Antimicrob Agents Chemother \n                           57, 1468\u20131473, https:\/\/doi.org\/10.1128\/AAC.02135-12 (2013).","journal-title":"Antimicrob Agents Chemother"},{"key":"17780_CR17","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1038\/nbt1267","volume":"24","author":"RE Hancock","year":"2006","unstructured":"Hancock, R. E. & Sahl, H. G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol \n                           24, 1551\u20131557, https:\/\/doi.org\/10.1038\/nbt1267 (2006).","journal-title":"Nat Biotechnol"},{"key":"17780_CR18","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1128\/AAC.49.1.316-322.2005","volume":"49","author":"B Deslouches","year":"2005","unstructured":"Deslouches, B. et al. De novo generation of cationic antimicrobial peptides: influence of length and tryptophan substitution on antimicrobial activity. Antimicrob Agents Chemother \n                           49, 316\u2013322, https:\/\/doi.org\/10.1128\/AAC.49.1.316-322.2005 (2005).","journal-title":"Antimicrob Agents Chemother"},{"key":"17780_CR19","doi-asserted-by":"publisher","first-page":"2511","DOI":"10.1128\/AAC.02218-12","volume":"57","author":"B Deslouches","year":"2013","unstructured":"Deslouches, B. et al. Rational design of engineered cationic antimicrobial peptides consisting exclusively of arginine and tryptophan, and their activity against multidrug-resistant pathogens. Antimicrob Agents Chemother \n                           57, 2511\u20132521, https:\/\/doi.org\/10.1128\/AAC.02218-12 (2013).","journal-title":"Antimicrob Agents Chemother"},{"key":"17780_CR20","doi-asserted-by":"publisher","first-page":"3208","DOI":"10.1128\/AAC.49.8.3208-3216.2005","volume":"49","author":"B Deslouches","year":"2005","unstructured":"Deslouches, B. et al. Activity of the de novo engineered antimicrobial peptide WLBU2 against Pseudomonas aeruginosa in human serum and whole blood: implications for systemic applications. Antimicrob Agents Chemother \n                           49, 3208\u20133216, https:\/\/doi.org\/10.1128\/AAC.49.8.3208-3216.2005 (2005).","journal-title":"Antimicrob Agents Chemother"},{"key":"17780_CR21","doi-asserted-by":"publisher","first-page":"2200","DOI":"10.1093\/jac\/dkw143","volume":"71","author":"LP Lashua","year":"2016","unstructured":"Lashua, L. P. et al. Engineered cationic antimicrobial peptide (eCAP) prevents Pseudomonas aeruginosa biofilm growth on airway epithelial cells. J Antimicrob Chemother \n                           71, 2200\u20132207, https:\/\/doi.org\/10.1093\/jac\/dkw143 (2016).","journal-title":"J Antimicrob Chemother"},{"key":"17780_CR22","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1093\/jac\/dkm253","volume":"60","author":"B Deslouches","year":"2007","unstructured":"Deslouches, B. et al. De novo-derived cationic antimicrobial peptide activity in a murine model of Pseudomonas aeruginosa bacteraemia. J Antimicrob Chemother \n                           60, 669\u2013672, https:\/\/doi.org\/10.1093\/jac\/dkm253 (2007).","journal-title":"J Antimicrob Chemother"},{"key":"17780_CR23","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1128\/AAC.03937-14","volume":"59","author":"B Deslouches","year":"2015","unstructured":"Deslouches, B. et al. Engineered cationic antimicrobial peptides to overcome multidrug resistance by ESKAPE pathogens. Antimicrob Agents Chemother \n                           59, 1329\u20131333, https:\/\/doi.org\/10.1128\/AAC.03937-14 (2015).","journal-title":"Antimicrob Agents Chemother"},{"key":"17780_CR24","doi-asserted-by":"publisher","unstructured":"Chen, C., Deslouches, B., Montelaro, R. C. & Di, Y. P. Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of P. aeruginosa pneumonia. Clin Microbiol Infect, https:\/\/doi.org\/10.1016\/j.cmi.2017.08.029 (2017).","DOI":"10.1016\/j.cmi.2017.08.029"},{"key":"17780_CR25","doi-asserted-by":"publisher","first-page":"5457","DOI":"10.1128\/JB.184.19.5457-5467.2002","volume":"184","author":"MJ Horsburgh","year":"2002","unstructured":"Horsburgh, M. J. et al. SigmaB modulates virulence determinant expression and stress resistance: characterization of a functional rsbU strain derived from Staphylococcus aureus 8325\u20134. J Bacteriol \n                           184, 5457\u20135467 (2002).","journal-title":"J Bacteriol"},{"key":"17780_CR26","doi-asserted-by":"publisher","first-page":"7116","DOI":"10.1128\/AEM.02636-13","volume":"79","author":"TK Wood","year":"2013","unstructured":"Wood, T. K., Knabel, S. J. & Kwan, B. W. Bacterial persister cell formation and dormancy. Appl Environ Microbiol \n                           79, 7116\u20137121, https:\/\/doi.org\/10.1128\/AEM.02636-13 (2013).","journal-title":"Appl Environ Microbiol"},{"key":"17780_CR27","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1159\/000342449","volume":"22","author":"S Lechner","year":"2012","unstructured":"Lechner, S., Lewis, K. & Bertram, R. Staphylococcus aureus persisters tolerant to bactericidal antibiotics. J Mol Microbiol Biotechnol \n                           22, 235\u2013244, https:\/\/doi.org\/10.1159\/000342449 (2012).","journal-title":"J Mol Microbiol Biotechnol"},{"key":"17780_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-319-09782-4_1","volume":"831","author":"BP Conlon","year":"2015","unstructured":"Conlon, B. P., Rowe, S. E. & Lewis, K. Persister cells in biofilm associated infections. Adv Exp Med Biol \n                           831, 1\u20139, https:\/\/doi.org\/10.1007\/978-3-319-09782-4_1 (2015).","journal-title":"Adv Exp Med Biol"},{"key":"17780_CR29","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1038\/nature12790","volume":"503","author":"BP Conlon","year":"2013","unstructured":"Conlon, B. P. et al. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature \n                           503, 365\u2013370, https:\/\/doi.org\/10.1038\/nature12790 (2013).","journal-title":"Nature"},{"key":"17780_CR30","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.1002\/bit.25963","volume":"113","author":"N Chowdhury","year":"2016","unstructured":"Chowdhury, N., Wood, T. L., Martinez-Vazquez, M., Garcia-Contreras, R. & Wood, T. K. DNA-crosslinker cisplatin eradicates bacterial persister cells. Biotechnol Bioeng \n                           113, 1984\u20131992, https:\/\/doi.org\/10.1002\/bit.25963 (2016).","journal-title":"Biotechnol Bioeng"},{"key":"17780_CR31","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1099\/jmm.0.030932-0","volume":"60","author":"M Fauvart","year":"2011","unstructured":"Fauvart, M., De Groote, V. N. & Michiels, J. Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies. J Med Microbiol \n                           60, 699\u2013709, https:\/\/doi.org\/10.1099\/jmm.0.030932-0 (2011).","journal-title":"J Med Microbiol"},{"key":"17780_CR32","doi-asserted-by":"publisher","first-page":"16051","DOI":"10.1038\/nmicrobiol.2016.51","volume":"1","author":"BP Conlon","year":"2016","unstructured":"Conlon, B. P. et al. Persister formation in Staphylococcus aureus is associated with ATP depletion. Nat Microbiol \n                           1, 16051, https:\/\/doi.org\/10.1038\/nmicrobiol.2016.51 (2016).","journal-title":"Nat Microbiol"},{"key":"17780_CR33","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1007\/s10930-013-9505-2","volume":"32","author":"G Carmona","year":"2013","unstructured":"Carmona, G., Rodriguez, A., Juarez, D., Corzo, G. & Villegas, E. Improved protease stability of the antimicrobial peptide Pin2 substituted with D-amino acids. Protein J \n                           32, 456\u2013466, https:\/\/doi.org\/10.1007\/s10930-013-9505-2 (2013).","journal-title":"Protein J"},{"key":"17780_CR34","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.1007\/s00726-015-2041-y","volume":"47","author":"A Di Grazia","year":"2015","unstructured":"Di Grazia, A. et al. D-Amino acids incorporation in the frog skin-derived peptide esculentin-1a(1-21)NH2 is beneficial for its multiple functions. Amino Acids \n                           47, 2505\u20132519, https:\/\/doi.org\/10.1007\/s00726-015-2041-y (2015).","journal-title":"Amino Acids"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17780-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17780-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17780-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T12:24:04Z","timestamp":1671798244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17780-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,22]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["17780"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-17780-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,22]]},"assertion":[{"value":"7 August 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 November 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"One of the co-authors, RCM, owns stock in Peptilogics which owns intellectual property on the main compound used in this study, WLBU2. The remainder of the authors have nothing to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"18098"}}