Design of Potent and Salt-Insensitive Antimicrobial Branched Peptides

• Published in: Polymers 2023-08, Vol.15 (17), p.3594
• Main Authors: To, Janet, Zhang, Xiaohong, Tam, James P
• Format: Article
• Language: English
• Subjects: Amines; Amino acids; Anti-infective agents; Antibiotics; Antimicrobial agents; Bacteria; Biopolymers; Drug resistance; Gram-positive bacteria; Lysine; Peptides; Polyamines; Polypeptides; Salt; Scaffolds; Solids
• ISSN: 2073-4360; 2073-4360
• DOI: 10.3390/polym15173594

Dendrimeric and branched peptides are polypeptides formed by diverse types of scaffolds to give them different forms. Previously, we reported a cascade-type, Lys-scaffolded antimicrobial peptide dendrimer D4R tethered with four RLYR tetrapeptides. Antimicrobial D4R is broad-spectrum, salt insensitive, and as potent as the natural-occurring tachyplesins, displaying minimum inhibitory concentrations (MIC) < 1 μM. However, the relationships between scaffolds and antimicrobial potency remain undefined. Here, we report the design of four novel types of peptide antimicrobials whose scaffolded backbones are lysine (Lys), iso-Lys, ornithine (Orn), or iso-Orn tethered with RLYR on their α- or sidechain-amines to give ε-, δ-, and their α-branched peptides. When assayed against ten microorganisms, the Lys-scaffolded α- and ε-branched peptides are broadly active, salt insensitive, and as potent as D4R and tachyplesins, whereas the corresponding Orn-scaffolded α- and δ-branched peptides are salt sensitive and much less potent, displaying MICs ranging from 1 to >500 μM. Structure-activity relationship studies suggested that Lys-scaffolds, but not Orn-scaffolds, can support a reverse turn to organize RLYR tetrapeptides as parallel β-strands to form an amphipathic structure with Leu-Tyr as a hydrophobic core. Together, these results provide a structural approach for designing potent and salt-insensitive dendrimeric or branched peptide antimicrobials.