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

Abstract

In the emerging era of antimicrobial resistance, the susceptibility to co-infections of patients suffering from either acquired or inherited hemolytic disorders can lead to dramatic increase in mortality rates. Closely related, heme liberated during hemolysis is one of the major sources of iron, which is vital for both host and invading microorganisms. While recent intensive research in the field has demonstrated that heme exerts diverse local effects including impairment of immune cells functions, it is almost completely unknown how it may compromise key molecules of our innate immune system, such as antimicrobial host defense peptides (HDPs). Since HDPs hold great promise as natural therapeutic agents against antibiotic-resistant microbes, understanding the effects that may modulate their action in microbial infection is crucial. Here we explore how hemin can interact directly with selected HDPs and influence their structure and membrane activity. It is revealed that induced helical folding, large assembly formation, and altered membrane activity is promoted by hemin. However, these effects showed variations depending mainly on peptide selectivity toward charged lipids, and the affinity of the peptide and hemin to lipid bilayers. Hemin-peptide complexes are sought to form semi-folded co-assemblies, which are present even with model membranes resembling mammalian or bacterial lipid compositions. In vitro cell-based toxicity assays supported that toxic effects of HDPs could be attenuated due to their assembly formation. These results are in line with our previous findings on peptide-lipid-small molecule systems suggesting that small molecules present in the complex in vivo milieu can regulate HDP function. Inversely, diverse effects of endogenous compounds could also be manipulated by HDPs.

Antibacterial Components and Modes of the Methanol-Phase Extract from Commelina communis Linn

“…Upon prolonged treatment for 4 h and 6 h, among the four strains, the most significant decrease in cell membrane fluidity was observed in the S. enterica ATCC15611 treatment group (4.80-fold and 5.66-fold) ( Figure 2 B). The change in membrane lipid composition may contribute to the observed membrane fluidity change by the therapeutic agents [ 18 ].…”

Antimicrobial Peptides—Mechanisms of Action, Antimicrobial Effects and Clinical Applications

“…Impaired membrane integrity occurs due to the interaction of AMP with a negatively charged cell membrane, inhibition of protein, DNA, and RNA synthesis, or interaction with specific intracellular targets [ 22 , 24 , 27 ]. The critical interaction points between the peptide and the bacterial membrane are electrostatic forces between the cationic AMPs and the negatively charged bacterial surface [ 28 , 29 , 30 ]. The cytoplasmic membranes of Gram-positive and Gram-negative bacteria are rich in phospholipids, phosphatidylglycerol, and cardiolipin, which have negatively charged major groups which strongly attract positively charged AMPs [ 1 , 31 ].…”

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

“…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.…”