Quorum Sensing Pseudomonas Quinolone Signal Forms Chiral Supramolecular Assemblies With the Host Defense Peptide LL-37

Abstract

Host defense antimicrobial peptides (HDPs) constitute an integral component of the innate immune system having nonspecific activity against a broad spectrum of microorganisms. They also have diverse biological functions in wound healing, angiogenesis, and immunomodulation, where it has also been demonstrated that they have a high affinity to interact with human lipid signaling molecules. Within bacterial biofilms, quorum sensing (QS), the vital bacterial cell-to-cell communication system, is maintained by similar diffusible small molecules which control phenotypic traits, virulence factors, biofilm formation, and dispersion. Efficient eradication of bacterial biofilms is of particular importance as these colonies greatly help individual cells to tolerate antibiotics and develop antimicrobial resistance. Regarding the antibacterial function, for several HDPs, including the human cathelicidin LL-37, affinity to eradicate biofilms can exceed their activity to kill individual bacteria. However, related underlying molecular mechanisms have not been explored yet. Here, we employed circular dichroism (CD) and UV/VIS spectroscopic analysis, which revealed that LL-37 exhibits QS signal affinity. This archetypal representative of HDPs interacts with the Pseudomonas quinolone signal (PQS) molecules, producing co-assemblies with peculiar optical activity. The binding of PQS onto the asymmetric peptide chains results in chiral supramolecular architectures consisting of helically disposed, J-aggregated molecules. Besides the well-known bacterial membrane disruption activity, our data propose a novel action mechanism of LL-37. As a specific case of the so-called quorum quenching, QS signal molecules captured by the peptide are sequestered inside co-assemblies, which may interfere with the microbial QS network helping to prevent and eradicate bacterial infections.

Stimuli-Responsive Membrane Anchor Peptide Nanofoils for Tunable Membrane Association and Lipid Bilayer Fusion

“…The 1-GLFD assembly formation can be most efficiently tracked by CD spectroscopy due to the chiral intermolecular exciton coupling between the respective π–π* transitions of the spiropyran chromophores. ICD signals can arise from both chiral and achiral molecules, including spiro compounds, where the packing results in a chiral supramolecular assembly such as for H-type or J-type aggregates . The packing of 1-GLFD molecules is likely such that the spiropyran units are positioned close to each other.…”

“…Inversely, the attenuation of specific fusion activity is also important as in the case of viral entry, where inhibitory membrane-active peptides, e.g., in the drug Fuzeon, demonstrate the potential of peptides interfering with membrane processes. As a natural inspiring example where peptidic self-assembly plays a key role in membrane manipulation, antimicrobial peptides often form temporary, assembled constructs that could be highly relevant for exerting toxicity on targets or for modulating other related biological functions. − Recently, it has also been indicated that the manipulation of their membrane activity and thus their antimicrobial affinity can also be achieved by the formation of functional supramolecular coassemblies. ,, However, these constructs often adopt only partially ordered assemblies, which limits their controlled use as functional materials.…”

Removal and identification of external protein corona members from RBC‐derived extracellular vesicles by surface manipulating antimicrobial peptides

“…The natural peptide interaction with mammalian EVs at these locations could aid cargo redistribution, whereas more membrane disrupting AMPs could disrupt EVs and release cytosolic components that are relevant for wound healing. On the other hand it is likely, that tethering bacterial EVs, which carry important components, such as compounds of quorum sensing, could be also relevant for exerting AMP antibiofilm activity (Hancock et al., 2021 ; Zsila et al., 2021 ).…”

Antimicrobial Mechanisms and Clinical Application Prospects of Antimicrobial Peptides

“…D-and L-LL-37 significantly downregulated the expression of the Rhl QS-related genes rhlA and rhlB in P. aeruginosa, inhibited the synthesis of rhamnosyltransferase, reduced biofilm formation, and degraded an existing P. aeruginosa biofilm [142]. LL-37 can also form supramolecular associations with Pseudomonas quinolone signal (PQS) molecules, another important component of the QS regulatory network of P. aeruginosa, and the QS signal molecules captured by the peptides are sequestered in coassemblies, thus helping to prevent and eradicate bacterial infection [143]. Gj-CATH2 has strong bactericidal and antibiofilm effects on Streptococcus mutans.…”