Hybrids made from antimicrobial peptides with different mechanisms of action show enhanced membrane permeabilization

Wade, Heidi M.; Darling, Louise E.O.; Elmore, Donald E.

doi:10.1016/j.bbamem.2019.05.002

Cited by 25 publications

(22 citation statements)

References 45 publications

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“…Chen, who conjugated the active domains of cecropin A and melittin to the elicitor harpin Hpa1 to obtain a chimeric protein that conserved the biological activities of the parent monomers [ 39 ]. In addition, few papers describing the design of new peptide conjugates have evaluated the effect on the activity of the order of the monomers in the sequence of these conjugates [ 13 , 40 , 41 , 42 , 43 ]. Results from this evaluation point out that the biological activity of the peptide conjugates is significantly sensitive to this structural modification.…”

Section: Introductionmentioning

confidence: 99%

“…Concerning the combination of two antimicrobial peptides, these mixtures have been reported to cause a higher antimicrobial effect than the individual components [ 18 , 45 , 46 , 47 , 48 ]. In this context, the differences in biological activity between the conjugation of two peptides in a single sequence and a mixture of the two individual peptides have been scarcely analyzed [ 43 , 49 , 50 , 51 , 52 ]. In one of these studies, it was concluded that a hybrid peptide derived from magainin 2 and PGLa showed similar or even stronger antimicrobial activity than an equimolar mixture of magainin and PGLa [ 49 ].…”

Section: Introductionmentioning

confidence: 99%

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A Bifunctional Peptide Conjugate That Controls Infections of Erwinia amylovora in Pear Plants

et al. 2021

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In this paper, peptide conjugates were designed and synthesized by incorporating the antimicrobial undecapeptide BP16 at the C- or N-terminus of the plant defense elicitor peptide flg15, leading to BP358 and BP359, respectively. The evaluation of their in vitro activity against six plant pathogenic bacteria revealed that BP358 displayed MIC values between 1.6 and 12.5 μM, being more active than flg15, BP16, BP359, and an equimolar mixture of BP16 and flg15. Moreover, BP358 was neither hemolytic nor toxic to tobacco leaves. BP358 triggered the overexpression of 6 out of the 11 plant defense-related genes tested. Interestingly, BP358 inhibited Erwinia amylovora infections in pear plants, showing slightly higher efficacy than the mixture of BP16 and flg15, and both treatments were as effective as the antibiotic kasugamycin. Thus, the bifunctional peptide conjugate BP358 is a promising agent to control fire blight and possibly other plant bacterial diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Bifunctional Peptide Conjugate That Controls Infections of Erwinia amylovora in Pear Plants

et al. 2021

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“…The antimicrobial peptide magainin 2 (MAG2, GIGKWLHSAKKFGKAFVGEIMNS), containing a F5W mutation for easier quantitation [ 29 ], was synthesized by Genscript with >95% purity. This exchange of a phenylalanine for a tryptophan does not alter the behavior of MAG2 [ 29 , 30 ]. Lyophilized MAG2 was rehydrated in water to make stock solutions, and the concentration of each stock solution was determined using the absorbance at 280 nm.…”

Section: Methodsmentioning

confidence: 99%

Extracellular Polymeric Substance Protects Some Cells in an Escherichia coli Biofilm from the Biomechanical Consequences of Treatment with Magainin 2

et al. 2021

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Bacterial biofilms have long been recognized as a source of persistent infections and industrial contamination with their intransigence generally attributed to their protective layer of extracellular polymeric substances (EPS). EPS, consisting of secreted nucleic acids, proteins, and polysaccharides, make it difficult to fully eliminate biofilms by conventional chemical or physical means. Since most bacteria are capable of forming biofilms, understanding how biofilms respond to new antibiotic compounds and components of the immune system has important ramifications. Antimicrobial peptides (AMPs) are both potential novel antibiotic compounds and part of the immune response in many different organisms. Here, we use atomic force microscopy to investigate the biomechanical changes that occur in individual cells when a biofilm is exposed to the AMP magainin 2 (MAG2), which acts by permeabilizing bacterial membranes. While MAG2 is able to prevent biofilm initiation, cells in an established biofilm can withstand exposure to high concentrations of MAG2. Treated cells in the biofilm are classified into two distinct populations after treatment: one population of cells is indistinguishable from untreated cells, maintaining cellular turgor pressure and a smooth outer surface, and the second population of cells are softer than untreated cells and have a rough outer surface after treatment. Notably, the latter population is similar to planktonic cells treated with MAG2. The EPS likely reduces the local MAG2 concentration around the stiffer cells since once the EPS was enzymatically removed, all cells became softer and had rough outer surfaces. Thus, while MAG2 appears to have the same mechanism of action in biofilm cells as in planktonic ones, MAG2 cannot eradicate a biofilm unless coupled with the removal of the EPS.

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“…However, this was not deemed as a cost-effective approach and the issue of host toxicity remains unresolved. Hybridization strategy was shown to circumvent these known issues, which involves the combination of key residues from two to three HDPs of different mechanisms of actions into a single sequence (109)(110)(111). In 1989, Boman et al (112) elegantly showed that a hybrid of cecropin-A (1-13) and melittin (1-13) was highly bactericidal and less toxic toward host cells compared to parent cecropin-A and melittin.…”

Section: Hybridizationmentioning

confidence: 99%

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

et al. 2020

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The golden era of antibiotics, heralded by the discovery of penicillin, has long been challenged by the emergence of antimicrobial resistance (AMR). Host defense peptides (HDPs), previously known as antimicrobial peptides, are emerging as a group of promising antimicrobial candidates for combatting AMR due to their rapid and unique antimicrobial action. Decades of research have advanced our understanding of the relationship between the physicochemical properties of HDPs and their underlying antimicrobial and non-antimicrobial functions, including immunomodulatory, anti-biofilm, and wound healing properties. However, the mission of translating novel HDP-derived molecules from bench to bedside has yet to be fully accomplished, primarily attributed to their intricate structure-activity relationship, toxicity, instability in host and microbial environment, lack of correlation between in vitro and in vivo efficacies, and dwindling interest from large pharmaceutical companies. Based on our previous experience and the expanding knowledge gleaned from the literature, this review aims to summarize the novel strategies that have been employed to enhance the antimicrobial efficacy, proteolytic stability, and cell selectivity, which are all crucial factors for bench-to-bedside translation of HDP-based treatment. Strategies such as residues substitution with natural and/or unnatural amino acids, hybridization, L-to-D heterochiral isomerization, C-and N-terminal modification, cyclization, incorporation with nanoparticles, and "smart design" using artificial intelligence technology, will be discussed. We also provide an overview of HDP-based treatment that are currently in the development pipeline.

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Hybrids made from antimicrobial peptides with different mechanisms of action show enhanced membrane permeabilization

Cited by 25 publications

References 45 publications

A Bifunctional Peptide Conjugate That Controls Infections of Erwinia amylovora in Pear Plants

A Bifunctional Peptide Conjugate That Controls Infections of Erwinia amylovora in Pear Plants

Extracellular Polymeric Substance Protects Some Cells in an Escherichia coli Biofilm from the Biomechanical Consequences of Treatment with Magainin 2

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

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