Anionic food color tartrazine enhances antibacterial efficacy of histatin-derived peptide DHVAR4 by fine-tuning its membrane activity

Abstract

Here it is demonstrated how some anionic food additives commonly used in our diet, such as tartrazine (TZ), bind to DHVAR4, an antimicrobial peptide (AMP) derived from oral host defense peptides, resulting in significantly fostered toxic activity against both Gram-positive and Gram-negative bacteria, but not against mammalian cells. Biophysical studies on the DHVAR4–TZ interaction indicate that initially large, positively charged aggregates are formed, but in the presence of lipid bilayers, they rather associate with the membrane surface. In contrast to synergistic effects observed for mixed antibacterial compounds, this is a principally different mechanism, where TZ directly acts on the membrane-associated AMP promoting its biologically active helical conformation. Model vesicle studies show that compared to dye-free DHVAR4, peptide–TZ complexes are more prone to form H-bonds with the phosphate ester moiety of the bilayer head-group region resulting in more controlled bilayer fusion mechanism and concerted severe cell damage. AMPs are considered as promising compounds to combat formidable antibiotic-resistant bacterial infections; however, we know very little on their in vivo actions, especially on how they interact with other chemical agents. The current example illustrates how food dyes can modulate AMP activity, which is hoped to inspire improved therapies against microbial infections in the alimentary tract. Results also imply that the structure and function of natural AMPs could be manipulated by small compounds, which may also offer a new strategic concept for the future design of peptide-based antimicrobials.

Interplay between membrane active host defense peptides and heme modulates their assemblies and in vitro activity

“…The short FK-16 showed an intermediate behaviour forming particles with both features. Similar morphology has already been observed for peptide associates formed with various binding partners such as LL-37 with RNA 47 , CM15 with the therapeutic drug suramin 21 , or Dhvar4 with the food colour tartrazine 23 . All these findings suggest that formation of such semi-folded assemblies might be common in interactions of amphipathic peptides with natural or synthetic small molecules.…”

“…AMPs along the gastro-intestinal tract were also considered, such as buforin I, a human gastric fluid AMP 39 , and Dhvar4, a potent AMP variant developed from human saliva histatins 40 . For the latter, interaction with food color small molecules affecting its membrane activity has been reported 23 . As reference, peptides already investigated for hemin interaction in the absence of lipid bilayers 19 such as the bee venom component melittin and its hybrid CM15 were also studied.…”

“…In this regard, helical conversion and assembly formation of AMPs could be induced by several sets of small molecules including synthetic dyes, marketed drugs, or even endogenous metabolites 17 – 20 . Related studies show that complex formation with the small molecule partners can result in blocking 21 , attenuating 22 , or even enhancing 23 peptide activity. This is contrasted to enhanced antimicrobial efficiency demonstrated with therapeutic antibiotics where peptides and small molecules act separately even when administered in combination 14 , 24 .…”

Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage

“…The pure lipid system was characterized by isolated, spherical-shaped,~100 nm-sized, unilamellar vesicles (Figure 4B), while the interaction with LL-37 promoted the contacts between the lipid vesicles, leading to a "shell-packed" morphology (Figure 4C) with a group of nearby vesicles enclosed in a shell-like envelope. Previous investigations on the cationic peptide DHVAR4 with anionic membranes showed similar behaviour, where small groups of closely located vesicles were embedded into larger shell-like structures [89].…”

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

“…Their actions also involve a variety of inflammatory and immunomodulatory responses ( Alba, Lopez-Abarrategui and Otero-Gonzalez 2012 ; Hancock et al, 2016 ). Moreover, besides their monomeric form, an increasing amount of data indicate that their supramolecular self- or co-assembled scaffolds can also have functional relevance ( Lee et al, 2019 ; Engelberg and Landau 2020 ; Ricci et al, 2020 ; Quemé-Peña et al, 2021 ). It has also been shown that various small organic molecules as well as lipid clusters trigger the disorder-to-order conformational transition of intrinsically unfolded AMPs, facilitating their oligomerization and complex formation, which can also affect the peptide function in vivo ( Ricci et al, 2020 ; Quemé-Peña et al, 2021 ).…”