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In this study we investigated the role of structurally conserved amino acids in reduced human defensin\u20055 (HD5<jats:sub>RED<\/jats:sub>), which is an endogenous peptide with antibacterial action and the ability to neutralize lipopolysaccharide (LPS). Cys residues and high Arg content, rather than Gly<jats:sup>18<\/jats:sup> and Arg<jats:sup>6<\/jats:sup>\u2013Glu<jats:sup>14<\/jats:sup>, were found to be indispensable for HD5<jats:sub>RED<\/jats:sub> binding to lipid\u2005A, for penetrating the bacterial outer and inner membranes, and for eliminating bacteria. Otherwise, all the conserved sites were requisite for HD5<jats:sub>RED<\/jats:sub> to block the interaction between LPS and LPS\u2010binding protein and to suppress the TLR4\u2013NF\u2010\u03baB signaling pathway initiated by LPS. Accordingly, we designed the acetamidomethylated <jats:sup>Acm<\/jats:sup>Cys\u2010E21R\u2010HD5<jats:sub>RED<\/jats:sub>, which was much more potent than HD5<jats:sub>RED<\/jats:sub> at eliminating bacteria and which can neutralize LPS. <jats:sup>Acm<\/jats:sup>Cys\u2010E21R\u2010HD5<jats:sub>RED<\/jats:sub> was also found to exhibit a synergistic effect with ciprofloxacin in killing multidrug\u2010resistant <jats:italic>Acinetobacter baumannii<\/jats:italic>. The results of this study, in which multifunctional AMPs were designed based on structure\u2013activity research, may help in the development of more peptide antibiotics.<\/jats:p>","DOI":"10.1002\/cmdc.201900282","type":"journal-article","created":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T05:59:57Z","timestamp":1562738397000},"page":"1457-1465","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Roles of the Conserved Amino Acid Residues in Reduced Human Defensin\u20055: Cysteine and Arginine Are Indispensable for Its Antibacterial Action and LPS Neutralization"],"prefix":"10.1002","volume":"14","author":[{"given":"Fang","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine Third Military Medical University  Chongqing 400038 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine Third Military Medical University  Chongqing 400038 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Xinqiao Hospital Third Military Medical University  Chongqing 400037 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine Third Military Medical University  Chongqing 400038 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junping","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine Third Military Medical University  Chongqing 400038 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5850-4533","authenticated-orcid":false,"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine Third Military Medical University  Chongqing 400038 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,10]]},"reference":[{"key":"e_1_2_8_1_1","first-page":"01504","author":"Wang C.","year":"2018","journal-title":"Antimicrob. 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