title: Design of a potent antibiotic peptide based on the active region of human defensin 5.
abstract: Human defensin 5 (HD5) is a broad-spectrum antibacterial peptide with a C-terminal active region. To promote the development of this peptide into an antibiotic, we initially substituted Glu21 with Arg because it is an electronegative residue located around the active region. Although detrimental to dimer formation, the E21R substitution markedly enhanced the antibacterial activity of HD5 and increased its ability to penetrate cell membranes, demonstrating that increasing the electropositive charge compensated for the effect of dimer disruption. Subsequently, a partial Arg scanning mutagenesis was performed, and Thr7 was selected for replacement with Arg to further strengthen the antibacterial activity. The newly designed peptide, T7E21R-HD5, exhibited potent antibacterial activity, even in saline and serum solutions. In contrast to monomeric E21R-HD5, T7E21R-HD5 assembled into an atypical dimer with parallel β strands, thus expanding the role of increasing electropositive charge in bactericidal activity and providing a useful guide for further defensin-derived antibiotic design.
authors.affiliation: †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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: †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.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Shen
authors.affiliation: ‡Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States.
authors.forename: Neelakshi
authors.initials: N
authors.lastname: Gohain
authors.affiliation: ‡Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Tolbert
authors.affiliation: †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.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: †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.
authors.forename: Naixin
authors.initials: N
authors.lastname: Zhang
authors.affiliation: †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.|§Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: †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.
authors.forename: Aiping
authors.initials: A
authors.lastname: Wang
authors.affiliation: †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.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Su
authors.affiliation: †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.
authors.forename: Tianmin
authors.initials: T
authors.lastname: Cheng
authors.affiliation: §Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: ‡Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States.
authors.forename: Marzena
authors.initials: M
authors.lastname: Pazgier
authors.affiliation: †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.
authors.forename: Junping
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D001120:Arginine; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D011487:Protein Conformation; D055503:Protein Multimerization; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D023084:alpha-Defensins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C500225:DEFA5 protein, human; D010455:Peptides; D023084:alpha-Defensins; D001120:Arginine