A Cyclic Antimicrobial Peptide Produced in Primate Leukocytes by the Ligation of Two Truncated α-Defensins

TLDR

RTD‑1 is produced by head‑to‑tail ligation of two α‑defensin–related nonapeptides, forming two new peptide bonds that generate the macrocyclic structure. Rhesus macaque neutrophils and monocytes contain an 18‑residue, tridisulfide macrocyclic peptide, RTD‑1, which is microbicidal at low micromolar concentrations, shows three‑fold greater antibacterial activity than an open‑chain analog, and requires the cyclic conformation for activity in 150 mM NaCl, illustrating that phagocytes synthesize and store such macrocyclic antibiotics.

Abstract

Analysis of rhesus macaque leukocytes disclosed the presence of an 18-residue macrocyclic, tridisulfide antibiotic peptide in granules of neutrophils and monocytes. The peptide, termed rhesus theta defensin-1 (RTD-1), is microbicidal for bacteria and fungi at low micromolar concentrations. Antibacterial activity of the cyclic peptide was threefold greater than that of an open-chain analog, and the cyclic conformation was required for antimicrobial activity in the presence of 150 millimolar sodium chloride. Biosynthesis of RTD-1 involves the head-to-tail ligation of two α-defensin–related nonapeptides, requiring the formation of two new peptide bonds. Thus, host defense cells possess mechanisms for synthesis and granular packaging of macrocyclic antibiotic peptides that are components of the phagocyte antimicrobial armamentarium.