X-ray structure of a carpet-like antimicrobial defensin–phospholipid membrane disruption complex

Järvå, Michael; Lay, Fung T.; Phan, Thanh Kha; Humble, Cassandra; Poon, Ivan K. H.; Bleackley, Mark R.; Anderson, Marilyn A.; Hulett, Mark D.; Kvansakul, Marc

doi:10.1038/s41467-018-04434-y

Cited by 56 publications

(51 citation statements)

References 49 publications

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“…Different authors have suggested several mechanisms for permeabilization of membranes [9,30]. In recent years some of the oligomeric structures of plant AMPs bound to their membrane target have been reported and their structures were deposited in the Protein Data Bank [20,[31][32][33]. We found that most of the peptides in our dataset were predicted to have at least one amyloidogenic region which strengthens our belief that these regions could help the AMPs to form oligomers.…”

Section: Oligomerization Of Ampssupporting

confidence: 84%

Plant Antibacterial Peptides and their Possible Oligomerization

Dutta¹,

Glyakina²,

Lahiri³

et al. 2018

Proceedings of the International Conference "Mathematical Biology and Bioinformatics"

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Plant antimicrobial peptides form an integral component of the innate immunity of plants and have activities against a broad spectrum of microorganisms. They were classified into various families and most share general features such as the presence of structure-stabilizing disulfide bridges and positive charge. Self-aggregation was suggested as one of the possible mechanisms for the effect of these antimicrobial peptides. Here, we have created a dataset comprising plant peptides with activity against gram positive and gram negative bacteria. We have found that the majority of the antibacterial peptides in this dataset contain at least one amyloidogenic region. We proposed that these amyloidogenic regions could help in the self-aggregation of the peptides and presented a possible ringlike oligomeric structure of the plant antimicrobial peptide NaD1.

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Section: Oligomerization Of Ampssupporting

confidence: 84%

Plant Antibacterial Peptides and their Possible Oligomerization

Dutta¹,

Glyakina²,

Lahiri³

et al. 2018

Proceedings of the International Conference "Mathematical Biology and Bioinformatics"

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“…Much research has focused on nano- and/or molecular-scale including models including the barrel-stave pore model, toroidal pore model, carpet model, and others by use of transmission electron microscopy, atomic force microscopy, and X-ray scattering. More recent work has highlighted the dynamic nature of some these states, possibly allowing for reversibility as seen in the FRAP data herein 5 , 7 , 53 – 55 . Other investigations into the mode of action of AMPs and their mimetics have also visualized dramatic, micrometer-scale membrane changes by electron microscopy and confocal microscopy 25 , 56 – 58 .…”

Section: Discussionmentioning

confidence: 97%

Antibacterial isoamphipathic oligomers highlight the importance of multimeric lipid aggregation for antibacterial potency

et al. 2018

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Cationic charge and hydrophobicity have long been understood to drive the potency and selectivity of antimicrobial peptides (AMPs). However, these properties alone struggle to guide broad success in vivo, where AMPs must differentiate bacterial and mammalian cells, while avoiding complex barriers. New parameters describing the biophysical processes of membrane disruption could provide new opportunities for antimicrobial optimization. In this work, we utilize oligothioetheramides (oligoTEAs) to explore the membrane-targeting mechanism of oligomers, which have the same cationic charge and hydrophobicity, yet show a unique ~ 10-fold difference in antibacterial potency. Solution-phase characterization reveals little difference in structure and dynamics. However, fluorescence microscopy of oligomer-treated Staphylococcus aureus mimetic membranes shows multimeric lipid aggregation that correlates with biological activity and helps establish a framework for the kinetic mechanism of action. Surface plasmon resonance supports the kinetic framework and supports lipid aggregation as a driver of antimicrobial function.

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“…In fact, most AMPs display high affinity for microbial membranes resulting from their overall amphipathic nature. Thus, it is not surprising that peptides from other structural classes such as defensins or cyclotides also exhibit potent membranolytic effects [55,56]. Nevertheless, it is becoming more apparent that membraneactive AMPs often act on specific targets rather than via unspecific pore formation.…”

Section: Insert Tablementioning

confidence: 99%

The Vast Structural Diversity of Antimicrobial Peptides

Koehbach

Craik

2019

Trends in Pharmacological Sciences

207

138

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Antimicrobial peptides (AMPs) occur in all kingdoms of life and are integral to host defense. They have diverse structures and target a variety of organisms, both by non-specific membrane interactions or via specific targets. Here we discuss the structures of AMPs from the four main classes currently recognized, i.e. peptides with (i) α-helical; (ii) β-sheet; (iii) αβ; and (iv) non-αβ elements as well as the growing pool of complex topologies including various post-translational modifications. We propose to group these latter peptides into a fifth class of AMPs. Such peptides exhibit high stability and amenability to chemical engineering, making them of interest for the development of novel antimicrobial agents. Advances and challenges in the development of these peptides towards therapeutic leads are presented. AMPsa diverse, but unifying strategy for defense Antimicrobial resistance has been identified as a major threat to public health and without immediate and global action the world is headed for a dangerous post-antibiotic era [1]. Thus, there is an urgent need for the development of novel antibiotic drugs to treat infectious diseases. In contrast to the rising numbers of multi drug resistant pathogens the rate of discovery of novel drug candidates is dwindling [2]. In this regard antimicrobial peptides (AMP) are a promising class of bioactive compounds that have attracted increasing attention over recent years. Their broad spectrum of activities extends beyond the killing of bacteria and fungi, with several AMPs also exhibiting antiviral [3], antiparasitic [4] or anticancer activities [5]. Furthermore, their multifaceted mechanisms-of-action potentially reduce their susceptibility to suffer from microbial resistance [6]. Starting in the 1980s, at a time when the numbers of novel antibacterial agents started to drop, the field of AMP research gained momentum when several novel examples were independently discovered across different species. These included peptides such as the cecropins from insects [7], the magainins from amphibians [8] and the mammalian defensins [9] to name a few. Since then a plethora of AMPs has been identified from all kingdoms of life, from bacteria to fungi to plants and animals. It is not only evident that these peptides play an integral part of an organism's innate defense machinery, but their variety also makes them a rich source for the discovery of potential novel drug leads. Their distribution among virtually all living organisms is complemented by their structural variety and range of antimicrobial activities. In this review we highlight this vast structural diversity of antimicrobial peptides. As well as providing a brief overview of the structures of well-known classes of AMPs, we introduce the growing class of structurally complex AMP topologies, in particular, cyclic and cysteine-rich defense peptides. We discuss recent progress and challenges in the characterization and development of peptide-based antibacterial molecules. 3 Structural classes of antimicrobial peptides Th...

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X-ray structure of a carpet-like antimicrobial defensin–phospholipid membrane disruption complex

Cited by 56 publications

References 49 publications

Plant Antibacterial Peptides and their Possible Oligomerization

Plant Antibacterial Peptides and their Possible Oligomerization

Antibacterial isoamphipathic oligomers highlight the importance of multimeric lipid aggregation for antibacterial potency

The Vast Structural Diversity of Antimicrobial Peptides

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