Improved antimicrobial peptides based on acyl-lysine oligomers

Radzishevsky, Inna; Rotem, Shahar; Bourdetsky, Dmitry; Navon-Venezia, Shiri; Carmeli, Yehuda; Mor, Amram

doi:10.1038/nbt1309

Cited by 243 publications

(302 citation statements)

References 15 publications

Supporting

Mentioning

288

Contrasting

Unclassified

Order By: Relevance

“…The development of membrane-active antimicrobial peptides as systemic agents for treatment of bacterial infections has been beset with difficulties associated with toxicity and tissue distribution, and few molecules have been shown to be active in vivo (37)(38)(39)(40). A widely used animal model for evaluating antimicrobial activity of preclinical compounds (41) is the thigh burden model, in which the thigh muscle of neutropenic mice is inoculated with bacteria, followed by i.v.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers

Choi

Isaacs

Clements³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

289

323

View full text Add to dashboard Cite

The emergence of drug-resistant bacteria has compromised the use of many conventional antibiotics, leading to heightened interest in a variety of antimicrobial peptides. Although these peptides have attractive potential as antibiotics, their size, stability, tissue distribution, and toxicity have hampered attempts to harness these capabilities. To address such issues, we have developed small (molecular mass <1,000 Da) arylamide foldamers that mimic antimicrobial peptides. Hydrogen-bonded restraints in the arylamide template rigidify the conformation via hydrogen bond formation and increase activity toward Staphylococcus aureus and Escherichia coli. The designed foldamers are highly active against S. aureus in an animal model. These results demonstrate the application of foldamer templates as therapeutics.antibiotic ͉ host defense peptide

show abstract

Section: Resultsmentioning

confidence: 99%

“…Flexible compounds can be highly potent, possibly because membranes induce an amphiphilic conformation in the bound state (25,40,44). In such cases, additional electrostatic and hydrophobic interactions might be necessary to compensate for the loss in conformational entropy of binding in such compounds.…”

Section: Discussionmentioning

confidence: 99%

De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers

Choi

Isaacs

Clements³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

289

323

View full text Add to dashboard Cite

show abstract

“…Hemolytic activity, however, was strongly linked to the presence of secondary structure. Disordered OAKs with butyl-and octyl-acyl moieties had hemolytic activities above 100 times the MIC hence presenting a certain advantage over natural dermaseptin (Radzishevsky et al, 2007). To contrast, longer acyl chains (>11 carbon atoms) presented higher flexibility, spontaneous aggregation and formation of amphipathic structures perturbing the membrane of red blood cells.…”

Section: I35 Tuning Physicochemical Properties and Selectivity: Olimentioning

confidence: 99%

“…The most potent OAK to date, C 12 K-7α 8 (MIC: 3.1 µg/mL against E. coli, Figure 1.13B) disrupts the cytoplasmic membrane , Epand et al, 2008, Radzishevsky et al, 2007 and has the ability to act synergistically with traditional antibiotics, raising the sensitivity of MDR bacteria . Shorter peptidomimetics such as C12(ω7)K-β12 (Figure 1.13C) were also active, but the mode of action was different from longer OAKs with a bacteriostatic effect (Sarig et al, 2010) unlike most AMPs which are bactericidal.…”

Section: I35 Tuning Physicochemical Properties and Selectivity: Olimentioning

confidence: 99%

“…Disordered OAKs with butyl-and octyl-acyl moieties had hemolytic activities above 100 times the MIC hence presenting a certain advantage over natural dermaseptin (Radzishevsky et al, 2007). To contrast, longer acyl chains (>11 carbon atoms) presented higher flexibility, spontaneous aggregation and formation of amphipathic structures perturbing the membrane of red blood cells.The most potent OAK to date, C 12 K-7α 8 (MIC: 3.1 µg/mL against E. coli, Figure 1.13B) disrupts the cytoplasmic membrane , Epand et al, 2008, Radzishevsky et al, 2007 and has the ability to act synergistically with traditional antibiotics, raising the sensitivity of MDR bacteria . Shorter peptidomimetics such as C12(ω7)K-β12 (Figure 1.13C) were also active, but the mode of action was different from longer OAKs with a bacteriostatic effect (Sarig et al, 2010) unlike most AMPs which are bactericidal.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Design, synthesis and evaluation of peptides and peptidomimetics inhibiting the bacterial DsbA-DsbB interaction

Duprez¹

View full text Add to dashboard Cite

The rapid development and dissemination of antibiotic resistance in pathogenic bacteria requires new strategies and new structural scaffolds of antimicrobial compounds to be investigated. A developing trend targets virulence factors rather than pathways essential for survival in an effort to neutralize pathogens while minimizing the risk of resistance. The thesis focuses on the design of new molecules from peptides to peptidomimetics aimed at disrupting the bacterial periplasmic oxidative system, a new antivirulence target.This thesis initially describes in chapter I the recent emergence of peptidomimetics in antimicrobial treatments aimed at well-known mechanisms as well as novel targets.Peptidomimetics may be particularly efficient for disrupting protein-protein interactions and have been successful for instance in preventing post-translational modifications or the formation of pili machinery. The thesis also highlights the mechanism and context of the interaction between DsbA and DsbB, both primary factors in the periplasmic oxidative system of gram-negative bacteria and the target proteins of this PhD.Developing inhibitors requires a solid screening pipeline of biophysical assays to measure binding parameters such as affinity, thermodynamics and kinetics. Chapter II highlights the building and optimization of such a pipeline by evaluating differential scanning fluorimetry, isothermal titration calorimetry, surface plasmon resonance, substrate oxidation assay and crystallography in order to characterize the designed peptide scaffolds.Chapter III focuses on the structure-activity relationship studies of 31 manually synthesized peptide sequences screened through this pipeline. Based on peptide length scouting, alanine scanning and rational substitution of specific residues, a final heptameric peptide was found to bind Escherichia coli DsbA with a Kd of 2.9 ± 0.3 µM. Moreover, the data suggest a probable disulfide bond formation between peptide and DsbA essential to the binding interface, while cysteine-free peptides present very weak affinity towards EcDsbA. This chapter generated a manuscript submitted to the Journal of Medicinal Chemistry.iiiIn a slightly different strategy, Chapter IV evaluates this best heptamer peptide sequence against a newly characterized Proteus Mirabilis DsbA, a structurally related protein (59% similarity with E. coli DsbA) showing promise for co-crystallization. With the peptide showing the same affinity against wild type E. coli and P. mirabilis DsbA, a highresolution (1.6 Å) co-crystal structure of the heptamer peptide bound to a cysteine mutant of P. mirabilis DsbA was solved. This structure shows the peptide binding to the P.mirabilis DsbA active site in a similar fashion to the native E. coli DsbA/DsbB interaction and differently from E. coli DsbA substrates. In-depth analysis of the high-resolution structure identifies two binding anchors, a H-bond-rich region and a hydrophobic pocket, which can be optimized for tighter affinities. This chapter generated a manuscript su...

show abstract

The Application of Cationic Antimicrobial Peptides in Cancer Treatment: Laboratory Investigations and Clinical Potential

Hilchie

2010

Emerging Cancer Therapy

View full text Add to dashboard Cite

Improved antimicrobial peptides based on acyl-lysine oligomers

Cited by 243 publications

References 15 publications

De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers

De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers

Design, synthesis and evaluation of peptides and peptidomimetics inhibiting the bacterial DsbA-DsbB interaction

The Application of Cationic Antimicrobial Peptides in Cancer Treatment: Laboratory Investigations and Clinical Potential

Contact Info

Product

Resources

About