title: A hybrid cationic peptide composed of human β-defensin-1 and humanized θ-defensin sequences exhibits salt-resistant antimicrobial activity.
abstract: We have designed a hybrid peptide by combining sequences of human β-defensin-1 (HBD-1) and θ-defensin, in an attempt to generate a molecule that combines the diversity in structure and biological activity of two different peptides to yield a promising therapeutic candidate. HBD-1 was chosen as it is a natural defensin of humans that is constitutively expressed, but its antibacterial activity is considerably impaired by elevated ionic strength. θ-Defensins are expressed in human bone marrow as a pseudogene and are homologous to rhesus monkey circular minidefensins. Retrocyclins are synthetic human θ-defensins. The cyclic nature of the θ-defensin peptides makes them salt resistant, nonhemolytic, and virtually noncytotoxic in vitro. However, a nonhuman circular molecule developed for clinical use would be less viable than a linear molecule. In this study, we have fused the C-terminal region of HBD-1 to the nonapeptide sequence of a synthetic retrocyclin. Cyclization was achieved by joining the terminal ends of the hybrid peptide by a disulfide bridge. The hybrid peptide with or without the disulfide bridge exhibited enhanced antimicrobial activity against both Gram-negative and Gram-positive bacteria as well as against fungi, including clinical bacterial isolates from eye infections. The peptide retained activity in the presence of NaCl and serum and was nonhemolytic in vitro. Thus, the hybrid peptide generated holds potential as a new class of antibiotics.
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India sudar1376@gmail.com.
authors.forename: Sudar
authors.initials: S
authors.lastname: Olli
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Ramakrishnan
authors.initials: R
authors.lastname: Nagaraj
authors.affiliation: Jhaveri Microbiology Centre, L. V. Prasad Eye Institute, Hyderabad, India.
authors.forename: Swapna R
authors.initials: SR
authors.lastname: Motukupally
mesh_terms: D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D002942:Circular Dichroism; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D053878:Hemolytic Agents / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry; D015202:Protein Engineering; D012965:Sodium Chloride / Q000494:pharmacology; D023084:alpha-Defensins / Q000737:chemistry; D023083:beta-Defensins / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; C429483:DEFA1A3 protein, human; C406407:DEFB1 protein, human; D053878:Hemolytic Agents; D010456:Peptides, Cyclic; D023084:alpha-Defensins; D023083:beta-Defensins; D012965:Sodium Chloride