{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T01:09:17Z","timestamp":1780103357585,"version":"3.54.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,6,7]],"date-time":"2018-06-07T00:00:00Z","timestamp":1528329600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,6,7]],"date-time":"2018-06-07T00:00:00Z","timestamp":1528329600000},"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><jats:p>Multidrug-resistant bacterial strains are a rapidly emerging healthcare threat; therefore it is critical to develop new therapies to combat these organisms. Prior antibacterial strategies directly target pathogen growth or viability. Host-directed strategies to increase antimicrobial defenses may be an effective alternative to antibiotics and reduce development of resistant strains. In this study, we demonstrated the efficacy of a pyrimidine synthesis inhibitor, <jats:italic>N<\/jats:italic>-phosphonacetyl-<jats:sc>l<\/jats:sc>-aspartate (PALA), to enhance clearance of methicillin-resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (MRSA)<jats:italic>, Pseudomonas aeruginosa<\/jats:italic>, and <jats:italic>Acinetobacter baumannii<\/jats:italic> strains by primary human dermal fibroblasts <jats:italic>in vitro<\/jats:italic>. PALA did not have a direct bactericidal effect, but enhanced cellular secretion of the antimicrobial peptides human \u03b2-defensin 2 (HBD2) and HBD3 from fibroblasts. When tested in porcine and human skin explant models, a topical PALA formulation was efficacious to enhance MRSA, <jats:italic>P. aeruginosa<\/jats:italic>, and <jats:italic>A. baumannii<\/jats:italic> clearance. Topical PALA treatment of human skin explants also resulted in increased HBD2 and cathelicidin (LL-37) production. The antimicrobial actions of PALA required expression of nucleotide-binding, oligomerization domain 2 (NOD2), receptor-interacting serine\/threonine-protein kinase 2 (RIP2), and carbamoyl phosphatase synthase II\/aspartate transcarbamylase\/dihydroorotase (CAD). Our results indicate that PALA may be a new option to combat multidrug-resistant bacterial infections of the skin through enhancement of an integral pathway of the cutaneous innate immune defense system.<\/jats:p>","DOI":"10.1038\/s41598-018-27012-0","type":"journal-article","created":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T09:22:40Z","timestamp":1527844960000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Pyrimidine synthesis inhibition enhances cutaneous defenses against antibiotic resistant bacteria through activation of NOD2 signaling"],"prefix":"10.1038","volume":"8","author":[{"given":"Samreen","family":"Jatana","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig R.","family":"Homer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Madajka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e1s K.","family":"Ponti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita","family":"Kabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Papay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6745-9487","authenticated-orcid":false,"given":"Christine","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,6,7]]},"reference":[{"key":"27012_CR1","doi-asserted-by":"publisher","first-page":"541340","DOI":"10.1155\/2014\/541340","volume":"2014","author":"J Tanwar","year":"2014","unstructured":"Tanwar, J., Das, S., Fatima, Z. & Hameed, S. Multidrug resistance: an emerging crisis. Interdiscip Perspect Infect Dis 2014, 541340, https:\/\/doi.org\/10.1155\/2014\/541340 (2014).","journal-title":"Interdiscip Perspect Infect Dis"},{"key":"27012_CR2","unstructured":"CDC. Antibiotic Resistance Threats in the United States, 2013. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services (2013)."},{"key":"27012_CR3","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1086\/533452","volume":"197","author":"LB Rice","year":"2008","unstructured":"Rice, L. B. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis 197, 1079\u20131081, https:\/\/doi.org\/10.1086\/533452 (2008).","journal-title":"J Infect Dis"},{"issue":"Suppl 1","key":"27012_CR4","doi-asserted-by":"publisher","first-page":"S7","DOI":"10.1086\/655995","volume":"31","author":"LB Rice","year":"2010","unstructured":"Rice, L. B. Progress and challenges in implementing the research on ESKAPE pathogens. Infect Control Hosp Epidemiol 31(Suppl 1), S7\u201310, https:\/\/doi.org\/10.1086\/655995 (2010).","journal-title":"Infect Control Hosp Epidemiol"},{"key":"27012_CR5","doi-asserted-by":"publisher","first-page":"2475067","DOI":"10.1155\/2016\/2475067","volume":"2016","author":"S Santajit","year":"2016","unstructured":"Santajit, S. & Indrawattana, N. Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens. Biomed Res Int 2016, 2475067, https:\/\/doi.org\/10.1155\/2016\/2475067 (2016).","journal-title":"Biomed Res Int"},{"key":"27012_CR6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1002\/wnan.1244","volume":"6","author":"S Jatana","year":"2014","unstructured":"Jatana, S. & DeLouise, L. A. Understanding engineered nanomaterial skin interactions and the modulatory effects of ultraviolet radiation skin exposure. Wiley Interdiscip Rev Nanomed Nanobiotechnol 6, 61\u201379, https:\/\/doi.org\/10.1002\/wnan.1244 (2014).","journal-title":"Wiley Interdiscip Rev Nanomed Nanobiotechnol"},{"issue":"32-38","key":"27012_CR7","doi-asserted-by":"publisher","first-page":"e38","DOI":"10.1111\/j.1365-3164.2012.01082.x","volume":"24","author":"M Afshar","year":"2013","unstructured":"Afshar, M. & Gallo, R. L. Innate immune defense system of the skin. Vet Dermatol 24(32-38), e38\u201339, https:\/\/doi.org\/10.1111\/j.1365-3164.2012.01082.x (2013).","journal-title":"Vet Dermatol"},{"key":"27012_CR8","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/nri2622","volume":"9","author":"FO Nestle","year":"2009","unstructured":"Nestle, F. O., Di Meglio, P., Qin, J. Z. & Nickoloff, B. J. Skin immune sentinels in health and disease. Nat Rev Immunol 9, 679\u2013691, https:\/\/doi.org\/10.1038\/nri2622 (2009).","journal-title":"Nat Rev Immunol"},{"key":"27012_CR9","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.it.2010.08.006","volume":"31","author":"DH Kaplan","year":"2010","unstructured":"Kaplan, D. H. In vivo function of Langerhans cells and dermal dendritic cells. Trends Immunol 31, 446\u2013451, https:\/\/doi.org\/10.1016\/j.it.2010.08.006 (2010).","journal-title":"Trends Immunol"},{"key":"27012_CR10","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1038\/ni.2680","volume":"14","author":"WR Heath","year":"2013","unstructured":"Heath, W. R. & Carbone, F. R. The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells. Nat Immunol 14, 978\u2013985, https:\/\/doi.org\/10.1038\/ni.2680 (2013).","journal-title":"Nat Immunol"},{"key":"27012_CR11","first-page":"8","volume":"135","author":"L O\u2019Neill","year":"2011","unstructured":"O\u2019Neill, L. Toll-like receptors and NOD-like receptors: key drivers of innate immunity and inflammation. Immunology 135, 8\u20138 (2011).","journal-title":"Immunology"},{"key":"27012_CR12","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1089\/wound.2012.0435","volume":"3","author":"N Strbo","year":"2014","unstructured":"Strbo, N., Yin, N. & Stojadinovic, O. Innate and Adaptive Immune Responses in Wound Epithelialization. Adv Wound Care (New Rochelle) 3, 492\u2013501, https:\/\/doi.org\/10.1089\/wound.2012.0435 (2014).","journal-title":"Adv Wound Care (New Rochelle)"},{"key":"27012_CR13","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1007\/s00109-008-0426-z","volume":"87","author":"J Kluwe","year":"2009","unstructured":"Kluwe, J., Mencin, A. & Schwabe, R. F. Toll-like receptors, wound healing, and carcinogenesis. J Mol Med (Berl) 87, 125\u2013138, https:\/\/doi.org\/10.1007\/s00109-008-0426-z (2009).","journal-title":"J Mol Med (Berl)"},{"key":"27012_CR14","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/nrmicro908","volume":"2","author":"BB Finlay","year":"2004","unstructured":"Finlay, B. B. & Hancock, R. E. Can innate immunity be enhanced to treat microbial infections? Nat Rev Microbiol 2, 497\u2013504, https:\/\/doi.org\/10.1038\/nrmicro908 (2004).","journal-title":"Nat Rev Microbiol"},{"key":"27012_CR15","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/nrd2783","volume":"8","author":"K Geddes","year":"2009","unstructured":"Geddes, K., Magalhaes, J. G. & Girardin, S. E. Unleashing the therapeutic potential of NOD-like receptors. Nat Rev Drug Discov 8, 465\u2013479, https:\/\/doi.org\/10.1038\/nrd2783 (2009).","journal-title":"Nat Rev Drug Discov"},{"key":"27012_CR16","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1053\/j.gastro.2012.02.040","volume":"142","author":"AL Richmond","year":"2012","unstructured":"Richmond, A. L. et al. The nucleotide synthesis enzyme CAD inhibits NOD2 antibacterial function in human intestinal epithelial cells. Gastroenterology 142, 1483\u20131492 e1486, https:\/\/doi.org\/10.1053\/j.gastro.2012.02.040 (2012).","journal-title":"Gastroenterology"},{"key":"27012_CR17","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1097\/MIB.0000000000000291","volume":"21","author":"Z Alnabhani","year":"2015","unstructured":"Alnabhani, Z. et al. Pseudomonas fluorescens alters the intestinal barrier function by modulating IL-1beta expression through hematopoietic NOD2 signaling. Inflamm Bowel Dis 21, 543\u2013555, https:\/\/doi.org\/10.1097\/MIB.0000000000000291 (2015).","journal-title":"Inflamm Bowel Dis"},{"key":"27012_CR18","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1128\/IAI.01459-13","volume":"82","author":"P Bist","year":"2014","unstructured":"Bist, P. et al. The Nod1, Nod2, and Rip2 axis contributes to host immune defense against intracellular Acinetobacter baumannii infection. Infect Immun 82, 1112\u20131122, https:\/\/doi.org\/10.1128\/IAI.01459-13 (2014).","journal-title":"Infect Immun"},{"key":"27012_CR19","doi-asserted-by":"publisher","first-page":"12873","DOI":"10.1073\/pnas.0904958106","volume":"106","author":"P Hruz","year":"2009","unstructured":"Hruz, P. et al. NOD2 contributes to cutaneous defense against Staphylococcus aureus through alpha-toxin-dependent innate immune activation. Proc Natl Acad Sci USA 106, 12873\u201312878, https:\/\/doi.org\/10.1073\/pnas.0904958106 (2009).","journal-title":"Proc Natl Acad Sci USA"},{"key":"27012_CR20","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/mi.2011.29","volume":"4","author":"W Strober","year":"2011","unstructured":"Strober, W. & Watanabe, T. NOD2, an intracellular innate immune sensor involved in host defense and Crohn\u2019s disease. Mucosal Immunol 4, 484\u2013495, https:\/\/doi.org\/10.1038\/mi.2011.29 (2011).","journal-title":"Mucosal Immunol"},{"key":"27012_CR21","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1002\/path.4095","volume":"229","author":"L Campbell","year":"2013","unstructured":"Campbell, L., Williams, H., Crompton, R. A., Cruickshank, S. M. & Hardman, M. J. Nod2 deficiency impairs inflammatory and epithelial aspects of the cutaneous wound-healing response. J Pathol 229, 121\u2013131, https:\/\/doi.org\/10.1002\/path.4095 (2013).","journal-title":"J Pathol"},{"key":"27012_CR22","doi-asserted-by":"publisher","first-page":"5414","DOI":"10.1074\/jbc.M709103200","volume":"283","author":"J Rohrl","year":"2008","unstructured":"Rohrl, J., Yang, D., Oppenheim, J. J. & Hehlgans, T. Identification and Biological Characterization of Mouse beta-defensin 14, the orthologue of human beta-defensin 3. J Biol Chem 283, 5414\u20135419, https:\/\/doi.org\/10.1074\/jbc.M709103200 (2008).","journal-title":"J Biol Chem"},{"key":"27012_CR23","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1074\/jbc.M511044200","volume":"281","author":"E Voss","year":"2006","unstructured":"Voss, E. et al. NOD2\/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 281, 2005\u20132011, https:\/\/doi.org\/10.1074\/jbc.M511044200 (2006).","journal-title":"J Biol Chem"},{"key":"27012_CR24","doi-asserted-by":"publisher","first-page":"rs3","DOI":"10.1126\/scisignal.2003305","volume":"6","author":"N Warner","year":"2013","unstructured":"Warner, N. et al. A genome-wide siRNA screen reveals positive and negative regulators of the NOD2 and NF-kappaB signaling pathways. Sci Signal 6, rs3, https:\/\/doi.org\/10.1126\/scisignal.2003305 (2013).","journal-title":"Sci Signal"},{"key":"27012_CR25","first-page":"6599","volume":"246","author":"KD Collins","year":"1971","unstructured":"Collins, K. D. & Stark, G. R. Aspartate transcarbamylase. Interaction with the transition state analogue N-(phosphonacetyl)-L-aspartate. J Biol Chem 246, 6599\u20136605 (1971).","journal-title":"Interaction with the transition state analogue N-(phosphonacetyl)-L-aspartate. J Biol Chem"},{"key":"27012_CR26","doi-asserted-by":"publisher","first-page":"e59232","DOI":"10.1371\/journal.pone.0059232","volume":"8","author":"RD Plaut","year":"2013","unstructured":"Plaut, R. D., Mocca, C. P., Prabhakara, R., Merkel, T. J. & Stibitz, S. Stably luminescent Staphylococcus aureus clinical strains for use in bioluminescent imaging. PLoS One 8, e59232, https:\/\/doi.org\/10.1371\/journal.pone.0059232 (2013).","journal-title":"PLoS One"},{"key":"27012_CR27","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1128\/IAI.00940-08","volume":"77","author":"HS Deshmukh","year":"2009","unstructured":"Deshmukh, H. S. et al. Critical role of NOD2 in regulating the immune response to Staphylococcus aureus. Infect Immun 77, 1376\u20131382, https:\/\/doi.org\/10.1128\/IAI.00940-08 (2009).","journal-title":"Infect Immun"},{"key":"27012_CR28","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1111\/j.1462-5822.2006.00878.x","volume":"9","author":"AJ Ratner","year":"2007","unstructured":"Ratner, A. J., Aguilar, J. L., Shchepetov, M., Lysenko, E. S. & Weiser, J. N. Nod1 mediates cytoplasmic sensing of combinations of extracellular bacteria. Cell Microbiol 9, 1343\u20131351, https:\/\/doi.org\/10.1111\/j.1462-5822.2006.00878.x (2007).","journal-title":"Cell Microbiol"},{"key":"27012_CR29","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.tips.2017.02.003","volume":"38","author":"J Munguia","year":"2017","unstructured":"Munguia, J. & Nizet, V. Pharmacological Targeting of the Host-Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs. Trends Pharmacol Sci 38, 473\u2013488, https:\/\/doi.org\/10.1016\/j.tips.2017.02.003 (2017).","journal-title":"Trends Pharmacol Sci"},{"key":"27012_CR30","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.micres.2016.04.008","volume":"191","author":"AC Rios","year":"2016","unstructured":"Rios, A. C. et al. Alternatives to overcoming bacterial resistances: State-of-the-art. Microbiol Res 191, 51\u201380, https:\/\/doi.org\/10.1016\/j.micres.2016.04.008 (2016).","journal-title":"Microbiol Res"},{"key":"27012_CR31","unstructured":"Antimicrobial Resistance: Tackling a Crisis for the Heath and Wealth of Nations., (HM Government, 2014)."},{"key":"27012_CR32","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/nrmicro2745","volume":"10","author":"RE Hancock","year":"2012","unstructured":"Hancock, R. E., Nijnik, A. & Philpott, D. J. Modulating immunity as a therapy for bacterial infections. Nat Rev Microbiol 10, 243\u2013254, https:\/\/doi.org\/10.1038\/nrmicro2745 (2012).","journal-title":"Nat Rev Microbiol"},{"key":"27012_CR33","doi-asserted-by":"publisher","first-page":"365","DOI":"10.2217\/imt.13.17","volume":"5","author":"ET Helbig","year":"2013","unstructured":"Helbig, E. T., Opitz, B. & Sander, L. E. Adjuvant immunotherapies as a novel approach to bacterial infections. Immunotherapy 5, 365\u2013381, https:\/\/doi.org\/10.2217\/imt.13.17 (2013).","journal-title":"Immunotherapy"},{"key":"27012_CR34","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.4049\/jimmunol.1000509","volume":"185","author":"FS Yu","year":"2010","unstructured":"Yu, F. S. et al. Flagellin stimulates protective lung mucosal immunity: role of cathelicidin-related antimicrobial peptide. J Immunol 185, 1142\u20131149, https:\/\/doi.org\/10.4049\/jimmunol.1000509 (2010).","journal-title":"J Immunol"},{"key":"27012_CR35","doi-asserted-by":"publisher","unstructured":"Williams, H. et al. Cutaneous Nod2 expression regulates the skin microbiome and wound healing in a murine model. J Invest Dermatol, https:\/\/doi.org\/10.1016\/j.jid.2017.05.029 (2017).","DOI":"10.1016\/j.jid.2017.05.029"},{"key":"27012_CR36","first-page":"376","volume":"90","author":"HC Polk Jr.","year":"1981","unstructured":"Polk, H. C. Jr. et al. Nonspecific enhancement of host defenses against infection: experimental evidence of a new order of efficacy and safety. Surgery 90, 376\u2013380 (1981).","journal-title":"Surgery"},{"key":"27012_CR37","first-page":"298","volume":"4","author":"IJ Fidler","year":"1985","unstructured":"Fidler, I. J., Brown, N. O. & Hart, I. R. Species variability for toxicity of free and liposome-encapsulated muramyl peptides administered intravenously. Journal of biological response modifiers 4, 298\u2013309 (1985).","journal-title":"Journal of biological response modifiers"},{"key":"27012_CR38","doi-asserted-by":"publisher","first-page":"7794","DOI":"10.1128\/JVI.74.17.7794-7802.2000","volume":"74","author":"EC Darcissac","year":"2000","unstructured":"Darcissac, E. C. et al. The synthetic immunomodulator murabutide controls human immunodeficiency virus type 1 replication at multiple levels in macrophages and dendritic cells. Journal of virology 74, 7794\u20137802 (2000).","journal-title":"Journal of virology"},{"key":"27012_CR39","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1097\/00126334-200207010-00005","volume":"30","author":"C Amiel","year":"2002","unstructured":"Amiel, C. et al. Clinical tolerance and immunologic effects after single or repeated administrations of the synthetic immunomodulator murabutide in HIV-1-infected patients. Journal of acquired immune deficiency syndromes (1999) 30, 294\u2013305 (2002).","journal-title":"Journal of acquired immune deficiency syndromes (1999)"},{"key":"27012_CR40","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1128\/AAC.02190-13","volume":"58","author":"L Hua","year":"2014","unstructured":"Hua, L. et al. Assessment of an anti-alpha-toxin monoclonal antibody for prevention and treatment of Staphylococcus aureus-induced pneumonia. Antimicrob Agents Chemother 58, 1108\u20131117, https:\/\/doi.org\/10.1128\/AAC.02190-13 (2014).","journal-title":"Antimicrob Agents Chemother"},{"key":"27012_CR41","unstructured":"Aridis Pharmaceuticals, I. NCT01589185 Safety, Pharmacokinetics and Efficacy of KBSA301 in Severe Pneumonia (S. Aureus). (2016)."},{"key":"27012_CR42","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1128\/AAC.04767-14","volume":"59","author":"D Kuo","year":"2015","unstructured":"Kuo, D. et al. Novel quorum-quenching agents promote methicillin-resistant Staphylococcus aureus (MRSA) wound healing and sensitize MRSA to beta-lactam antibiotics. Antimicrob Agents Chemother 59, 1512\u20131518, https:\/\/doi.org\/10.1128\/AAC.04767-14 (2015).","journal-title":"Antimicrob Agents Chemother"},{"key":"27012_CR43","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1128\/AAC.36.1.167","volume":"36","author":"O Tatara","year":"1992","unstructured":"Tatara, O., Nakahama, C. & Niki, Y. Synergistic effects of romurtide and cefmenoxime against experimental Klebsiella pneumonia in mice. Antimicrob Agents Chemother 36, 167\u2013171 (1992).","journal-title":"Antimicrob Agents Chemother"},{"key":"27012_CR44","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/35106587","volume":"414","author":"V Nizet","year":"2001","unstructured":"Nizet, V. et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414, 454\u2013457, https:\/\/doi.org\/10.1038\/35106587 (2001).","journal-title":"Nature"},{"key":"27012_CR45","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1182\/blood.V97.1.297","volume":"97","author":"AM Cole","year":"2001","unstructured":"Cole, A. M. et al. Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds. Blood 97, 297\u2013304 (2001).","journal-title":"Blood"},{"key":"27012_CR46","first-page":"11","volume":"8","author":"V Nizet","year":"2006","unstructured":"Nizet, V. Antimicrobial peptide resistance mechanisms of human bacterial pathogens. Curr Issues Mol Biol 8, 11\u201326 (2006).","journal-title":"Curr Issues Mol Biol"},{"key":"27012_CR47","doi-asserted-by":"publisher","first-page":"9178","DOI":"10.1073\/pnas.0602888103","volume":"103","author":"R Raqib","year":"2006","unstructured":"Raqib, R. et al. Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc Natl Acad Sci USA 103, 9178\u20139183, https:\/\/doi.org\/10.1073\/pnas.0602888103 (2006).","journal-title":"Proc Natl Acad Sci USA"},{"key":"27012_CR48","doi-asserted-by":"publisher","first-page":"e0138340","DOI":"10.1371\/journal.pone.0138340","volume":"10","author":"A Mily","year":"2015","unstructured":"Mily, A. et al. Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial. PLoS One 10, e0138340, https:\/\/doi.org\/10.1371\/journal.pone.0138340 (2015).","journal-title":"PLoS One"},{"key":"27012_CR49","unstructured":"Bergman, P. NCT02178488 Efficacy Study of Vitamin D Supplementation to Meticillin Resistant Staphylococcus Aureus (MRSA) Carriers (D-STAPH). ClinicalTrials.gov (2017)."},{"key":"27012_CR50","unstructured":"International Centre for Diarrhoeal Disease Research, B. NCT00800930 Therapeutic Induction of EndogenousAntibiotics. ClinicalTrials.gov (2011)."},{"key":"27012_CR51","doi-asserted-by":"publisher","first-page":"4411","DOI":"10.1128\/AAC.02554-14","volume":"58","author":"EM Haisma","year":"2014","unstructured":"Haisma, E. M. et al. LL-37-derived peptides eradicate multidrug-resistant Staphylococcus aureus from thermally wounded human skin equivalents. Antimicrob Agents Chemother 58, 4411\u20134419, https:\/\/doi.org\/10.1128\/AAC.02554-14 (2014).","journal-title":"Antimicrob Agents Chemother"},{"key":"27012_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/srep29707","volume":"6","author":"MF Mohamed","year":"2016","unstructured":"Mohamed, M. F., Abdelkhalek, A. & Seleem, M. N. Evaluation of short synthetic antimicrobial peptides for treatment of drug-resistant and intracellular Staphylococcus aureus. Sci Rep 6, 29707, https:\/\/doi.org\/10.1038\/srep29707 (2016).","journal-title":"Sci Rep"},{"key":"27012_CR53","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.sder.2008.04.002","volume":"27","author":"TR Hata","year":"2008","unstructured":"Hata, T. R. & Gallo, R. L. Antimicrobial peptides, skin infections, and atopic dermatitis. Semin Cutan Med Surg 27, 144\u2013150, https:\/\/doi.org\/10.1016\/j.sder.2008.04.002 (2008).","journal-title":"Semin Cutan Med Surg"},{"key":"27012_CR54","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1111\/j.0022-202X.2004.23443.x","volume":"124","author":"MH Braff","year":"2005","unstructured":"Braff, M. H., Di Nardo, A. & Gallo, R. L. Keratinocytes store the antimicrobial peptide cathelicidin in lamellar bodies. J Invest Dermatol 124, 394\u2013400, https:\/\/doi.org\/10.1111\/j.0022-202X.2004.23443.x (2005).","journal-title":"J Invest Dermatol"},{"key":"27012_CR55","first-page":"11","volume":"18","author":"K Yamasaki","year":"2008","unstructured":"Yamasaki, K. & Gallo, R. L. Antimicrobial peptides in human skin disease. European Journal of Dermatology 18, 11\u201321 (2008).","journal-title":"European Journal of Dermatology"},{"key":"27012_CR56","doi-asserted-by":"publisher","first-page":"40301","DOI":"10.1074\/jbc.M508538200","volume":"280","author":"C McDonald","year":"2005","unstructured":"McDonald, C. et al. A role for Erbin in the regulation of Nod2-dependent NF-kappa B signaling. J Biol Chem 280, 40301\u201340309, https:\/\/doi.org\/10.1074\/jbc.M508538200 (2005).","journal-title":"J Biol Chem"},{"key":"27012_CR57","doi-asserted-by":"publisher","first-page":"7071","DOI":"10.4049\/jimmunol.1000110","volume":"184","author":"WKE Ip","year":"2010","unstructured":"Ip, W. K. E. et al. Phagocytosis and Phagosome Acidification Are Required for Pathogen Processing and MyD88-Dependent Responses to Staphylococcus aureus. Journal of Immunology 184, 7071\u20137081, https:\/\/doi.org\/10.4049\/jimmunol.1000110 (2010).","journal-title":"Journal of Immunology"},{"key":"27012_CR58","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402\u2013408, https:\/\/doi.org\/10.1006\/meth.2001.1262 (2001).","journal-title":"Methods"},{"key":"27012_CR59","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1053\/j.gastro.2010.07.006","volume":"139","author":"CR Homer","year":"2010","unstructured":"Homer, C. R., Richmond, A. L., Rebert, N. A., Achkar, J. P. & McDonald, C. ATG16L1 and NOD2 Interact in an Autophagy-Dependent Antibacterial Pathway Implicated in Crohn\u2019s Disease Pathogenesis. Gastroenterology 139, 1630\u20131641.e2, https:\/\/doi.org\/10.1053\/j.gastro.2010.07.006 (2010).","journal-title":"Gastroenterology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27012-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27012-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27012-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T06:11:40Z","timestamp":1671603100000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27012-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,7]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["27012"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-27012-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,7]]},"assertion":[{"value":"2 October 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 May 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 June 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"8708"}}