A Hybrid Cationic Peptide Composed of Human beta -Defensin-1 and Humanized [thetas]-Defensin Sequences Exhibits Salt-Resistant Antimicrobial Activity

• Published in: Antimicrobial agents and chemotherapy Vol. 59; no. 1; pp. 217 - 225
• Main Authors: Olli, Sudar, Nagaraj, Ramakrishnan, Motukupally, Swapna R
• Format: Journal Article
• Language: English
• Published: 01.01.2015
• Subjects: Macaca mulatta
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.03901-14

We have designed a hybrid peptide by combining sequences of human beta -defensin-1 (HBD-1) and [thetas]-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. [thetas]-Defensins are expressed in human bone marrow as a pseudogene and are homologous to rhesus monkey circular minidefensins. Retrocyclins are synthetic human [thetas]-defensins. The cyclic nature of the [thetas]-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.