The Sushi peptides: structural characterization and mode of action against Gram-negative bacteria

Abstract

The compositional difference in microbial and human cell membranes allows antimicrobial peptides to preferentially bind microbes. Peptides which specifically target lipopolysaccharide (LPS) and palmitoyl-oleoyl-phosphatidylglycerol (POPG) are efficient antibiotics. From the core LPS-binding region of Factor C, two 34-mer Sushi peptides, S1 and S3, were derived. S1 functions as a monomer, while S3 is active as a dimer. Both S1 and S3 display detergent-like properties in disrupting LPS aggregates, with specificity for POPG resulting from electrostatic and hydrophobic forces between the peptides and the bacterial lipids. During interaction with POPG, the S1 transitioned from a random coil to an alpha-helix, while S3 resumed a mixture of alpha-helix and beta-sheet structures. The unsaturated nature of POPG confers fluidity and enhances insertion of the peptides into the lipid bilayer, causing maximal disruption of the bacterial membrane. These parameters should be considered in designing and developing new generations of peptide antibiotics with LPS-neutralizing capability.

Identification of Cell-Penetrating Peptides That Are Bactericidal to Neisseria meningitidis and Prevent Inflammatory Responses upon Infection

“…This effect correlated with reduced binding of LPS to TP10-treated macrophages and was unrelated to its bactericidal activity. Endotoxin-neutralizing activity has been described for certain AMPs and peptides derived from diverse LPS-binding proteins (53)(54)(55)(56). Similar to TP10, the peptide antibiotic polymyxin B is able to inhibit the inflammatory action of LPS both in vitro and in vivo (57,58).…”

Identification of lipopolysaccharide‐binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model

“…In the current study, we demonstrated that HMGB1 has two LPS-binding motifs located in its A and B box domains respectively, and that two synthetic peptides (HPep1 and HPep6) containing each of these LPS-binding motifs respectively, can inhibit LPS-stimulated TNF-α production both ex vivo in human PBMCs and in vivo in a mouse model of subclinical endotoxemia. Peptides derived from several LBPs, namely LBP, bactericidal/permeability-increasing protein, limulus anti-LPS factor [21], serum amyloid protein [22, 23], lactoferrin [24], cationic protein (CAP)18 [25], and CAP37 [26] antagonize LPS (review [27, 28]). To this list, we can now add the two novel HMGB1-derived peptides HPep1 and HPep6.…”

Dual functionality nanobioconjugates targeting intracellular bacteria in cancer cells with enhanced antimicrobial activity

“…Quantification of the extent of drug binding allowed us to determine the optimum drug loading required for achieving the highest antibacterial activity amongst all the NP-bioconjugates. Sushi peptides are biologically-active derivatives of the widely popular factor C protein found in horseshoe crabs 32 . Factor C proteins are extensively used in endotoxin detection assays such as the popular endotoxin test such as LAL tests 33, 34 .…”