Experimental concepts for linking the biological activities of antimicrobial peptides to their molecular modes of action

Malanovic, Nermina; Marx, Lisa; Blondelle, Sylvie E.; Pabst, Georg; Semeraro, Enrico F.

doi:10.1016/j.bbamem.2020.183275

Cited by 28 publications

(26 citation statements)

References 126 publications

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“…According to this model, designed antimicrobial compounds accumulate at the surface of the negatively charged membranes of bacteria or cancer cells. With increasing peptide concentration, transient micron-sized openings [ 108 ] can form in the membrane due to fluctuations in the local peptide-to-lipid ratio [ 111 ], allowing peptide translocation or the passage of other species [ 110 , 114 , 115 , 116 ].…”

Section: Resultsmentioning

confidence: 99%

Molecular Basis of the Anticancer and Antibacterial Properties of CecropinXJ Peptide: An In Silico Study

Ramos‐Martín

D’Amelio

2021

IJMS

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Esophageal cancer is an aggressive lethal malignancy causing thousands of deaths every year. While current treatments have poor outcomes, cecropinXJ (CXJ) is one of the very few peptides with demonstrated in vivo activity. The great interest in CXJ stems from its low toxicity and additional activity against most ESKAPE bacteria and fungi. Here, we present the first study of its mechanism of action based on molecular dynamics (MD) simulations and sequence-property alignment. Although unstructured in solution, predictions highlight the presence of two helices separated by a flexible hinge containing P24 and stabilized by the interaction of W2 with target biomembranes: an amphipathic helix-I and a poorly structured helix-II. Both MD and sequence-property alignment point to the important role of helix I in both the activity and the interaction with biomembranes. MD reveals that CXJ interacts mainly with phosphatidylserine (PS) but also with phosphatidylethanolamine (PE) headgroups, both found in the outer leaflet of cancer cells, while salt bridges with phosphate moieties are prevalent in bacterial biomimetic membranes composed of PE, phosphatidylglycerol (PG) and cardiolipin (CL). The antibacterial activity of CXJ might also explain its interaction with mitochondria, whose phospholipid composition recalls that of bacteria and its capability to induce apoptosis in cancer cells.

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Section: Resultsmentioning

confidence: 99%

Molecular Basis of the Anticancer and Antibacterial Properties of CecropinXJ Peptide: An In Silico Study

Ramos‐Martín

D’Amelio

2021

IJMS

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“…Reflecting on such controversies, Wimley and Hristova ( 2 ) formulated almost 10 years ago several unanswered questions relating to AMP activity studies in model membrane systems and microbes. Answering these questions is often challenged by the different experimental windows and sensitivities of the applied techniques ( 21 ). Here, focusing on the lactoferricin derivatives LF11-215 (H-FWRIRIRR-NH 2 ) and LF11-324 (H-PFFWRIRIRR-NH 2 ), we set out to address three of these questions: (i) How are vesicle leakage and microbial killing correlated?…”

Section: Introductionmentioning

confidence: 99%

Bridging the Antimicrobial Activity of Two Lactoferricin Derivatives in E. coli and Lipid-Only Membranes

Marx

Semeraro

Mandl

et al. 2021

Front. Med. Technol.

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We coupled the antimicrobial activity of two well-studied lactoferricin derivatives, LF11-215 and LF11-324, in Escherichia coli and different lipid-only mimics of its cytoplasmic membrane using a common thermodynamic framework for peptide partitioning. In particular, we combined an improved analysis of microdilution assays with ζ-potential measurements, which allowed us to discriminate between the maximum number of surface-adsorbed peptides and peptides fully partitioned into the bacteria. At the same time, we measured the partitioning of the peptides into vesicles composed of phosphatidylethanolamine (PE), phosphatidylgylcerol (PG), and cardiolipin (CL) mixtures using tryptophan fluorescence and determined their membrane activity using a dye leakage assay and small-angle X-ray scattering. We found that the vast majority of LF11-215 and LF11-324 readily enter inner bacterial compartments, whereas only 1−5% remain surface bound. We observed comparable membrane binding of both peptides in membrane mimics containing PE and different molar ratios of PG and CL. The peptides' activity caused a concentration-dependent dye leakage in all studied membrane mimics; however, it also led to the formation of large aggregates, part of which contained collapsed multibilayers with sandwiched peptides in the interstitial space between membranes. This effect was least pronounced in pure PG vesicles, requiring also the highest peptide concentration to induce membrane permeabilization. In PE-containing systems, we additionally observed an effective shielding of the fluorescent dyes from leakage even at highest peptide concentrations, suggesting a coupling of the peptide activity to vesicle fusion, being mediated by the intrinsic lipid curvatures of PE and CL. Our results thus show that LF11-215 and LF11-324 effectively target inner bacterial components, while the stored elastic stress makes membranes more vulnerable to peptide translocation.

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“…The unique combinations of hydrophilic and hydrophobic amino acids in AMP-sequences are structurally segregated to confer them the ability to solubilize both in lipid-rich and aqueous environments. 6,13 In addition, many AMPs display a preference for lipid-liquid disordered domains similar to amyloid proteins. 12 Lengthwise, most AMPs fall in the range of peptides containing 12-50 amino acid residues.…”

Section: Introductionmentioning

confidence: 99%

Structural and functional swapping of amyloidogenic and antimicrobial peptides: Redefining the role of amyloidogenic propensity in disease and host defense

Yadav

2021

Journal of Peptide Science

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Peptides constitute an essential component of all organisms' protein homeostasis ranging from bacteria, plants, and animals. They have organically been evolved to perform a wide range of essential functions, including their role as neurotransmitters, antimicrobial peptides (AMPs), and hormones. AMPs are short peptides synthesized by almost all organisms, implicated in guarding the host from various microbial infections. Their inherent ability to differentiate the target microbes from the host confers them excellent prospects in fighting against microbial infections and affirming their robust therapeutic potential against numerous drug-resistant microbes. Amyloidogenic peptides (AMYs) represent another class of short peptides armed with inherent aggregation propensity and form fibrillar aggregates rich in cross β-sheet structure. They are often involved in various degenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and type-2 diabetes. Although these two distinct classes of peptides (i.e., AMPs and AMYs) appear to be functionally divergent, recent studies suggest that they possess a significant degree of structural and functional reciprocity. Consistent with this, many AMPs display amphiphilic nature, and hence, they can facilitate membrane remodeling processes, such as pore formation and fusion, similar to AMYs. The mounting evidence suggests the inherent ability of AMPs to self-assemble to form amyloid-like structures. On the other hand, the demonstration of antimicrobial properties of AMYs in their monomeric conformation provides a hint about the existence of an evolutionary linkage between these two classes of peptides. The congregation of specific amino acids to form aggregation-prone regions in a protein/peptide might have served as an evolutionary reservoir from which AMPs and AMYs were consecutively evolved. The current article reviews the fundamental features of the AMPs, AMYs, and their inter-relatedness and emerging paradigm for their inter-conversion.

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Experimental concepts for linking the biological activities of antimicrobial peptides to their molecular modes of action

Cited by 28 publications

References 126 publications

Molecular Basis of the Anticancer and Antibacterial Properties of CecropinXJ Peptide: An In Silico Study

Molecular Basis of the Anticancer and Antibacterial Properties of CecropinXJ Peptide: An In Silico Study

Bridging the Antimicrobial Activity of Two Lactoferricin Derivatives in E. coli and Lipid-Only Membranes

Structural and functional swapping of amyloidogenic and antimicrobial peptides: Redefining the role of amyloidogenic propensity in disease and host defense

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