Interactions of two enantiomers of a designer antimicrobial peptide with structural components of the bacterial cell envelope

Abstract

Antimicrobial peptides (AMPs) have great potential in treating multi-drug resistant bacterial infections. The antimicrobial activity of D-enantiomers is significantly higher than L-enantiomers and sometimes selectively enhanced against Gram-positive bacteria. Unlike phospholipids in the bacterial plasma membrane, the role of other bacterial cell envelop components is often overlooked in the mode of action of AMPs. In this work, we explored the structural interactions between the main different structural components in Gram-negative/Gram-positive bacteria and the two enantiomers of a designer AMP, GL13K. We observed that both L-GL13K and D-GL13K formed self-assembled amyloid-like nanofibrils when the peptides interacted with lipopolysaccharide and lipoteichoic acid, components of the outer membrane of Gram-negative bacteria and cell wall of Gram-positive bacteria, respectively. Another cell wall component, peptidoglycan, showed strong interactions exclusively with D-GL13K and formed distinct laminar structures. This specific interaction between peptidoglycans and D-GL13K might contribute to the enhanced activity of D-GL13K against Gram-positive bacteria as they have a much thicker peptidoglycan layer than Gram-negative bacteria. A better understanding of the specific role of bacterial cell envelop components in the AMPs mechanism of action can guide the design of more effective Gram-selective AMPs.

The antimicrobial peptide DGL13K is active against drug-resistant gram-negative bacteria and sub-inhibitory concentrations stimulate bacterial growth without causing resistance

“…The circular dichroism and NMR structures of LGL13K have been resolved in phospholipid environments that mimicked those of bacterial membranes [ 31 , 32 ]. Once the peptide reaches the cell membrane, it transitions from random coil, through α-helix, to a ß-sheet structure that presumably represents the active conformation.…”

“…The ß-sheet structure aligns with model membranes and has a high capacity to disrupt membrane order [ 31 ]. Analysis of DGL13K secondary structure suggests that its interaction with LPS-rich (Gram negative-like) membranes is similar to that of LGL13K [ 32 ]. In this context the negative charge of the target membrane attracts the higher concentrations of the cationic peptide needed for ß-sheet formation and membrane perturbation [ 31 ].…”

Present status and future directions of intracanal medicaments

“…The very simple example was the combination of two common intracanal medicaments; examples included the combinations of AMPs with intracanal irrigants (Tong et al, 2014), chitosan with chlorhexidine gluconate (Savitha et al, 2019), and AgNPs with chlorhexidine gluconate (Charannya et al, 2018). The nanocomposites of AMP-AgNP had a significant increase in antimicrobial activity compared with either single AMP or single AgNP (Pal et al, 2016(Pal et al, , 2019Ruden et al, 2009;Ye et al, 2022). This might be attributed to the synergistic effect that AMPs create by inducing bacterial transmembrane pore formation for the access of AgNPs to the internal targets.…”

“…Several models have been proposed to introduce the concept of transmembrane pore formation leading to bacterial lysis, including ‘barrel‐stave’, ‘carpet’ and ‘toroidal‐pore’ models (Brogden, 2005). Ye and co‐workers studied the relationships between the antimicrobial activity and the self‐assembly of AMPs using a model AMP, GL13K, derived from a human parotid secretory protein (Ye & Aparicio, 2019, 2022; Ye et al, 2021). In their studies, the peptides with higher potency in forming self‐assembled nanofibers presented stronger antimicrobial activity, which might be caused by the strong interactions between the self‐assembled AMPs and the bacterial lipid bilayer and other cell envelope components.…”

Bioinspired Anti-demineralization Enamel Coating for Orthodontics

“…In this work, for the first time, we coated enamel with self-assembled peptide amphiphiles to prevent demineralization from orthodontic treatment by leveraging its dual functions (i.e., its antimicrobial activity and reduced acid permeability). We used a D-enantiomer of GL13K (D-GL13K), which was composed of all D-amino acids (Ye et al 2018; Ye and Aparicio 2022) to increase the coating’s antimicrobial activity and resistance to proteolytic enzymes.…”