De novo generation of short antimicrobial peptides with enhanced stability and cell specificity

Kim, Hyun; Jang, Ju Hye; Kim, Sun Chang; Cho, Ju Hyun

doi:10.1093/jac/dkt322

Cited by 185 publications

(131 citation statements)

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“…In particular, DP7 showed the strongest antimicrobial activity to both standard microbial strains and isolated antibiotic-resistant strains, while displaying lower cytotoxicity to human erythrocytes, HEK 293 cells, and human epithelial fibroblast cells. Unlike most AMPs, which form pores in the cytoplasmic membrane that lead to cell lysis or leakage of the cytoplasm (19,23,24), Bac2A has been reported to kill S. aureus without cell lysis, but cross-wall formation was affected (25). As a derivative of Bac2A, DP7 is also a liner peptide (26)(27)(28), but it appears to operate via a distinct mechanism (Fig.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of Antimicrobial Peptides Developed Using an Amino Acid-Based Activity Prediction Method

Wang

et al. 2014

Antimicrob Agents Chemother

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cTo design and discover new antimicrobial peptides (AMPs) with high levels of antimicrobial activity, a number of machinelearning methods and prediction methods have been developed. Here, we present a new prediction method that can identify novel AMPs that are highly similar in sequence to known peptides but offer improved antimicrobial activity along with lower host cytotoxicity. Using previously generated AMP amino acid substitution data, we developed an amino acid activity contribution matrix that contained an activity contribution value for each amino acid in each position of the model peptide. A series of AMPs were designed with this method. After evaluating the antimicrobial activities of these novel AMPs against both Gram-positive and Gram-negative bacterial strains, DP7 was chosen for further analysis. Compared to the parent peptide HH2, this novel AMP showed broad-spectrum, improved antimicrobial activity, and in a cytotoxicity assay it showed lower toxicity against human cells. The in vivo antimicrobial activity of DP7 was tested in a Staphylococcus aureus infection murine model. When inoculated and treated via intraperitoneal injection, DP7 reduced the bacterial load in the peritoneal lavage solution. Electron microscope imaging and the results indicated disruption of the S. aureus outer membrane by DP7. Our new prediction method can therefore be employed to identify AMPs possessing minor amino acid differences with improved antimicrobial activities, potentially increasing the therapeutic agents available to combat multidrug-resistant infections.A ntimicrobial peptides (AMPs) are produced by multicellular organisms to defend against microbial infections. Along with potent antimicrobial activity, many AMPs also have the ability to enhance immunity by functioning as immunomodulators (1-3). AMPs therefore have excellent therapeutic potential, especially in light of increased drug resistance to many conventional antibiotic therapies. A number of naturally occurring peptides and synthetic derivatives have been developed or are currently in development (2, 4-6). Although AMPs vary in length, amino acid composition, and structure, they share some similarities, such as electrical charge and amphipathicity (3, 7). To determine the characteristics that are important in antimicrobial activity, bioinformatic tools and prediction methods have been developed (8), all based to some extent on the sequence similarities between peptides (9-11).To optimize the antimicrobial activity of identified AMPs and to predict novel peptide sequences, we present a machine-learning method based on the concept of an antimicrobial activity contribution score for each amino acid. Here, we consider that each amino acid in a peptide sequence possesses a different level of importance for the biological activity of that peptide, and this is represented by an assigned score. By calculation of each amino acid's contribution score, we can predict the antimicrobial activity of an AMP.To verify our results, we tested some of our designed AMPs ...

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of Antimicrobial Peptides Developed Using an Amino Acid-Based Activity Prediction Method

Wang

et al. 2014

Antimicrob Agents Chemother

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“…For instance, antimicrobial agents are often tested in lab-DOI: 10.1159/000491497 oratory conditions such as Mueller Hinton broth (MHB), and other nutrient rich laboratory media, which is not physiologically relevant [10,43], while many AMPs have been tested for efficacy in phosphate buffer, which is also non-physiological. Many parameters such as carbon and nitrogen sources, iron availability, and divalent cation concentrations differ significantly in lab media or buffers from those in an infected host [10,45,46]. HDPs exposed to components of plasma, serum, saliva, mucus, or urine for example, often exhibit very different activity levels from those in lab media for various reasons [24,27,[46][47][48][49].…”

Section: Challenges Facing Clinical Application Of Anti-biofilm Peptidesmentioning

confidence: 99%

“…Many parameters such as carbon and nitrogen sources, iron availability, and divalent cation concentrations differ significantly in lab media or buffers from those in an infected host [10,45,46]. HDPs exposed to components of plasma, serum, saliva, mucus, or urine for example, often exhibit very different activity levels from those in lab media for various reasons [24,27,[46][47][48][49]. Furthermore, the environment in which a bacterium grows can substantially affect the biofilm architecture and alter anti-biofilm peptide binding and/or penetration [45].…”

Section: Challenges Facing Clinical Application Of Anti-biofilm Peptidesmentioning

confidence: 99%

Design and Assessment of Anti-Biofilm Peptides: Steps Toward Clinical Application

Dostert¹,

Belanger²,

Hancock³

2018

J Innate Immun

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Highly antibiotic resistant, microbial communities, referred to as biofilms, cause various life-threatening infections in humans. At least two-thirds of all clinical infections are biofilm associated, and antibiotic therapy regularly fails to cure patients. Anti-biofilm peptides represent a promising approach to treat these infections by targeting biofilm-specific characteristics such as highly conserved regulatory mechanisms. They are being considered for clinical application and we discuss here key factors in discovery, design, and application, particularly the implementation of host-mimicking conditions, that are required to enable the successful advancement of potent anti-biofilm peptides from the bench to the clinic.

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“…As a means to increase protease stability without the use of costly unnatural amino acids and complicated synthetic schemes, Kim et al have recently performed the de novo design of 15 amino acids long amphipathic α-helical folding AMPs with systematic rearrangement of naturally occurring L-amino acids to avoid protease-scissile sites [132]. To limit peptide bond hydrolysis by trypsin, which cleaves at the C-terminal side of cationic Lys and Arg residues ( between two Lys residues (K 11 and K 13 ) as it has been reported that no proteolytic cleavage by trypsin occurs if Pro is on the carboxyl side of the cleavage site while a slower rate of hydrolysis occurs if an acidic residue is on either side.…”

Section: Rational Rearrangement Of Amino Acids To Avoid Protease Cleamentioning

confidence: 99%

Strategies employed in the design and optimization of synthetic antimicrobial peptide amphiphiles with enhanced therapeutic potentials

Ong

Wiradharma

Yang

2014

Advanced Drug Delivery Reviews

255

217

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De novo generation of short antimicrobial peptides with enhanced stability and cell specificity

Abstract: This study suggests that GNU6 and GNU7 might overcome serious problems that currently prevent the clinical use of AMPs and be developed as novel antimicrobial agents.

Cited by 185 publications

References 50 publications

In Vitro and In Vivo Activities of Antimicrobial Peptides Developed Using an Amino Acid-Based Activity Prediction Method

In Vitro and In Vivo Activities of Antimicrobial Peptides Developed Using an Amino Acid-Based Activity Prediction Method

Design and Assessment of Anti-Biofilm Peptides: Steps Toward Clinical Application

Strategies employed in the design and optimization of synthetic antimicrobial peptide amphiphiles with enhanced therapeutic potentials

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