Resurrecting Inactive Antimicrobial Peptides from the Lipopolysaccharide Trap

Abstract

Host defense antimicrobial peptides (AMPs) are a promising source of antibiotics for the treatment of multiple-drug-resistant pathogens. Lipopolysaccharide (LPS), the major component of the outer leaflet of the outer membrane of Gram-negative bacteria, functions as a permeability barrier against a variety of molecules, including AMPs. Further, LPS or endotoxin is the causative agent of sepsis killing 100,000 people per year in the United States alone. LPS can restrict the activity of AMPs inducing aggregations at the outer membrane, as observed for frog AMPs, temporins, and also in model AMPs. Aggregated AMPs, "trapped" by the outer membrane, are unable to traverse the cell wall, causing their inactivation. In this work, we show that these inactive AMPs can overcome LPS-induced aggregations while conjugated with a short LPS binding ␤-boomerang peptide motif and become highly bactericidal. The generated hybrid peptides exhibit activity against Gram-negative and Gram-positive bacteria in high-salt conditions and detoxify endotoxin. Structural and biophysical studies establish the mechanism of action of these peptides in LPS outer membrane. Most importantly, this study provides a new concept for the development of a potent broad-spectrum antibiotic with efficient outer membrane disruption as the mode of action.

Pseudomonas aeruginosa Psl Exopolysaccharide Interacts with the Antimicrobial Peptide LG21

“…It is observed that in the control simulation, the LG21 peptide is majorly found as a random coil structure. Previous experimental studies based on NMR and CD-spectra also observed that LG21 is a hybrid antimicrobial peptide that exists in a random-coil conformation in aqueous solution [29,30]. From Table 1, it is also observed that for the simulation system with Psl, the percentage of α-helix (≈0.26) is substantially higher than the one observed in the control simulation (≈0.05), which clearly demonstrates that interaction of LG21 with Psl induces the helicity.…”

Oligopolyphenylenevinylene-Conjugated Oligoelectrolyte Membrane Insertion Molecules Selectively Disrupt Cell Envelopes of Gram-Positive Bacteria

“…Additionally, the outer membrane of Gram-negative organisms incorporates a negatively charged lipopolysaccharide (LPS) layer that acts as a molecular sieve, impeding the passage of small molecules across the cellular envelope. The protective effect of the Gram-negative OM to certain antibiotics is well documented (17,(22)(23)(24).…”

“…The tight packing of the six fatty acid components of lipid A of the LPS layer is thought to underlie the impervious nature of the Gram-negative OM (23,24). A range of E. coli mutants, which have profound defects in the lipid A component of the LPS in the OM, have a phenotype that is described as deep rough.…”

A Novel RNase 3/ECP Peptide for Pseudomonas aeruginosa Biofilm Eradication That Combines Antimicrobial, Lipopolysaccharide Binding, and Cell-Agglutinating Activities

“…Recent insights into AMP interactions with LPS indicate that binding to the bacterium's outer membrane does not guarantee the peptide subsequent membrane-permeabilizing action. On the contrary, LPS may induce peptide aggregation at the cell wall, acting as an inactivating trap and impeding access to the cytoplasmic membrane (59). Indeed, a recent biophysical approach toward the underlying AMP structural requirements for biofilm eradication pointed to a delicate balance between peptidebacterium adhesion and self-oligomerization (12).…”